Transcript Metagenic’s Seminar 3, 2003 Clinical Workshop

Digestions and
Detoxification
By
Stephen Eddey
M.H.Sc.,B.H.Sc.,Dip.App.Sc.,Ass.Dip.App.Sc.,Cert.I.V.(Workplace and
Training).
Principal
Health Schools Australia
Digestion - Stomach
Acid is the key to optimal stomach digestion.
Arginine boost blood flow to the stomach
and increases stomach acid.
Brzozowski, T., et al.
Role of L-arginine, a substrate for nitric oxidesynthase, in gastroprotection and ulcer healing.
Journal of
Gastroenterology. 32(4):442-452, 1997.
Glutamine Boosts Stomach
acids
These results show that a Gln-enriched
enteral diet increased splanchnic blood
flow, which was not mediated by
pancreatic glucagon or increased nitric
oxide production as determined by urinary
nitrate excretion.
Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic
blood flow in the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.
Ginger Protects the Stomach
“The results of this study demonstrate that the extract in
the dose of 500 mg/kg orally exert highly significant
cytoprotection against 80% ethanol, 0.6M HC1, 0.2M
NaOH and 25% NaCl induced gastric lesions. The
extract also prevented the occurrence of gastric ulcers
induced by non-steroidal anti-inflammatory drugs
(NSAIDs) and hypothermic restraint stress. These
observations suggest cytoprotective and antiulcerogenic effect of the ginger.”
Al-Yahya, M. A., et al. Gastro protective activity of ginger in albino rats. Am J Chinese
Med. 17(1-2):51-56, 1989.
Glutamine Increases Blood
Flow to the Pancreas
“In the glutamine-enriched group, higher organ blood
flows were measured in the stomach (51%), the
pancreas (35%), small intestine (32%), and colon
(55%), compared with controls. No differences were
found in systemic hemodynamic parameters between
the control and Gln-supplemented groups.
Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic blood flow in
the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.
The Liver: Why is it so big?
Biotransformation
Biotransformation is the metabolic alteration
of toxins and other chmicals by phase 1
(cytochrome P450) and phase 2
(conjugating) enzymes.
These enzymes are involved in both the
synthesis of steroid hormones, and the
clearance (detoxification) of harmful
endogenous and exogenous compounds.
Biotransformational activation
of substrates
“Human beings are faced with a
continuous burden of reactive chemical
entities that are formed during
biotransformation
of
foreign
compounds,
as
well
as
from
endogenous molecules.”
Rinaldi R. Reactive intermediates and the dynamics of glutathione
transferases. Drug Metab Disp. 2002;30:1053-1058.
Biotransformational activation
of substrates
“Many developmental toxicants and
teratogens require prior metabolism to
reactive species or free radicals to exert
toxicity. Thus the knowledge of
conceptal
biotransformation
is
absolutely critical in understanding
toxicity of these chemicals”
Kulkarni AP. Role of biotransformation in conceptal toxicity of drugs and
other chemicals. Curr Pharm Des. 2001 Jun;7(9):833-57.
BIOTRANSFORMATION IS A
PROTECTIVE MECHANISM
“Along
with
strategies
such
as
sequestration, scavenging and binding,
catalytic biotransformation evolved as
an important biochemical protection
mechanism against toxic chemical
species.”
Sheehan D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem J 2001;360:1-16
ENZYMES MEDIATE
BIOTRANSFORMATION
“Cells possess an impressive array of
enzymes capable of biotransforming a
wide range of different chemical
structures and functionalities.”
Sheehan, D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem. J. 2001; 360: 1-16
BIOTRANSFORMATION IS
IMPERATIVE FOR SURVIVAL
The perpetuation of human and other
animal species depends, among other
factors, on successful defence against
the deleterious effects of naturally
occurring toxic chemicals in plants and
synthetic toxicants.”
Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of
endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825
UNDERSTANDING
BIOTRANSFORMATION
IMPROVES DRUG THERAPY
“biotransformation represents a key
element
in
understanding
the
pharmacological efficacy of drugs and
the toxicity (of) pesticides, industrial/
environmental chemicals, and naturally
occurring toxicants”
Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of
endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825
THE PHASES OF
DETOXIFICATION
The enzymic detoxification of xenobiotics
has been classified into two distinct
phases which act in a tightly integrated
manner.
Sheehan, D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem. J. 2001; 360: 1-16
Phase I & II detoxification
THE ROLE OF PHASE I
“Phase I is catalysed mainly by the
cytochrome P450 system. This family
of microsomal proteins is responsible
for a range of reactions, of which
oxidation appears to be the most
important”
Sheehan, D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem. J. 2001; 360: 1-16
THE ROLE OF PHASE II
“Phase II enzymes catalyse the
conjugation of activated xenobiotics to
an endogenous water-soluble substrate,
such as reduced glutathione (GSH),
UDP-glucuronic acid or glycine”
Sheehan, D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem. J. 2001; 360: 1-16
Phytonutrients regulate
biotransformation
“Induction
or
inhibition
of
biotransformational enzymes, enzymes
that activate or detoxify numerous
xenobiotics, is one mechanism by which
vegetables may alter cancer risk.”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000; 21(6):1157-62
BIOTRANSFORMATIONAL
ENZYMES
“Biotransformation enzymes, such as the
cytochrome P450 (CYP) isoenzymes,
are essential for initiating conversion of
lipophilic
xenobiotics
into
more
hydrophilic, water-soluble metabolites.”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000; 21(6):1157-62
Functions of Cytochrome P450
Enzymes
• The synthesis and degradation of
endogenous steroid hormones, vitamins
and fatty acid derivatives
• Metabolism of drugs, environmental
pollutants and carcinogens.
Honkakoski P. Regulation of cytochrome P450 (CYP) genes by nuclear
receptors. Biochem J 2000;347:321-337
THE IMPORTANCE OF
BIOTRANSFORMATION
“They (CYP) reduce the half-life of and
duration of exposure to xenobiotics and
prevent accumulation of the parent
compounds.”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000; 21(6):1157-62
Phase 1 Detoxification
Biotransformational enzymes
“Cytochrome
p450’s
support
the
oxidative, peroxidative and reductive
metabolism of such endogenous and
xenobiotic substrates as environmental
pollutants,
agrochemicals,
plant
allelochemicals,
steroids,
prostaglandins and fatty acids.”
Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution
and drug metabolism in humans. Curr Drug Metab. 2002 Dec;3(6):56197
Biotransformational enzymes
“They also display complex sex-, tissueand development-specific expression
patterns which are controlled by
hormones or growth factors, suggesting
that these CYPs may have critical roles,
not only in elimination of endobiotic
signalling molecules, but also in their
production.”
Honkakoski, P. et. al. Regulation of cytochrome P450 (CYP) genes by
nuclear receptors. Biochem J. 2000;347:321-337.
Factors Affecting Phase 1 and
Phase 2 Detoxification
The
two
principle
phases
of
biotransformation are susceptible to
induction and/or inhibition by two
major factors;
1. Gene polymorphisms leading variable
enzyme action and slow and fast
metabolisers
2. Environmental
factors
–
both
exogenous and endogenous
Phase 2 Detoxification
Phase II enzymes
“The induction of phase II enzymes is
considered an important mechanism of
protection against chemical stress and
carcinogenesis.”
Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione Stransferase Ya subunit gene is controlled by an electrophile-responsive
element. Proc. Nat. Acad. Sci. USA. 1990;87:6258-6262
Phase 2 Detoxification Processes
• Sulphation
• Glucuronidation
• Glutathionation
• Acetylation
• Methylation
• Glycination
GSTs ARE THE MAJOR PHASE
II ENZYMES
“The glutathione transferases (GST’s:
also
known
as
glutathione-Stransferases) are major phase II
detoxification enzymes found mainly in
the cytosol”
Sheehan, D. Structure, function and evolution of glutathione transferases:
implications for classification of non-mammalian members of an ancient
enzyme superfamily. Biochem. J. 2001; 360: 1-16
Glutathione transferase
“The primary defence of nature against
electrophiles occurs by glutathione
transferase
(GST)
catalysed
conjugation to glutathione.”
Rinaldi, R. Reactive intermediates and the dynamics of glutathione
transferases. Drug Metab Disp. 2002;30:1053-1058
Glutathione transferase
The glutathione S-transferases (GST)
belong to a group of xenobiotic
metabolising phase II enzymes that
function as intracellular detoxification
systems of mutagens, carcinogens, and
other toxic compounds
Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione Stransferase Ya subunit gene is controlled by an electrophile-responsive
element. Proc Nat Acad Sci 1990;87:6258-6262
GST LEVELS DECREASE
PROCARCINOGENS
“it is well documented that the proportion
of
reactive
benzo(a)pyrene
diol
epoxides reacting with DNA in a cellular
system is directly related to the amount
and nature of glutathione transferases
present.”
Rinaldi R. Reactive intermediates and the dynamics of glutathione
transferases. Drug Metabolism and Disposition 2002;30(10):1053-58
Prevalence of GSTM1 & GSTT1
Polymorphisms
The range of GSTM1 & GSTT1 null
genotype frequencies range from 40% 50% and from 10%-65% in Western and
Asian countries, respectively.
Lin J et al. Glutathione S-Transferase M1 and T1 genotypes and
endometriosis risk: a case controlled study. Chin Med J
2003;116(5):777-780
GSTM1 & GSTT1
polymorphisms increase
environmental disease risk
“Both GSTM1 and GSTT1 genetic
polymorphisms
have
been
demonstrated to affect susceptibility to
various
cancers,
and
may
be
considered as risk modifiers for various
environmentally induced diseases.”
Jun, L. et. al. Glutathione-S-transferase M1 and T1 genotypes and
endometriosis risk: a case controlled study. Chin Med J
2003;116(5):777-780
PHASE II ENZYME
DEFICIENCY IN
ENDOMETRIOSIS
“We suggest the involvement of both NAT2
(acetylation) and GSTM1 (glutathione
conjugation) detoxification system genes
in the pathogenesis of endometriosis and
the possible impact of NAT2 gene
polymorphism in the development of
different forms of this disease.”
Baranova, H. Possible involvement of arylamine N-acetyltransferase 2,
glutathione-s-transferases M1 and T1 genes in the development of
endometriosis. Mol Hum Reprod 1999;5(7):636-41
grapefruit
GRAPEFRUIT JUICE
DOWNREGULATES CYP3A4 IN
THE SMALL INTESTINE
“the effect of grapefruit juice on oral
felodipine kinetics is its selective downregulation of CYP3A4 in the small
intestine”
Lown K et al. Grapefruit juice increases felodipine oral availability in
humans by decreasing intestinal CYP3A4 protein expression. J Clin
Invest 1997;99: 2545-53
GRAPEFRUIT JUICE ALTERS
DRUG METABOLISM
“A single glass of grapefruit juice has
been shown to significantly increase the
oral availability of a variety of commonly
used medications”
Lown K et al. Grapefruit juice increases felodipine oral availability in
humans by decreasing intestinal CYP3A4 protein expression. J Clin
Invest 1997;99: 2545-53
Hypericum
HYPERICUM ALTERS
PHARMACOKINETICS
“Recent clinical studies demonstrate the
hypericum
extracts
increase
the
metabolism of various drugs, including
combined
oral
contraceptives,
cyclosporin and indinavir.”
Moore, L. St. John’s Wort induces hepatic drug metabolism through
activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June
20; 97(13):7500-2
HYPERICUM INDUCES CYP3A4
EXPRESSION
“Treatment of primary human hepatocytes
with hypericum extracts or hyperiforin
results in a marked induction of
CYP3A4 expression.”
Moore, L. St. John’s Wort induces hepatic drug metabolism through
activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June
20; 97(13):7500-2
HYPERICUM ALTERS
PHARMACOKINETICS
“Because CYP3A4 is involved in the oxidative
metabolism of 50% of all drugs, our findings
provide a molecular mechanism for the
interaction of St. John’s wort with drugs and
suggest that hypericum extracts are likely to
interact with many more drugs than
previously had been realised.”
Moore, L. St. John’s Wort induces hepatic drug metabolism through
activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June
20; 97(13):7500-2
Kava-Kava
Kava-Kava inhibits CYP3A4
activity
“extracts of kava-kava contain
various inhibitors of CYP3A4 and
are
likely
to
cause
drug
interactions when administered
concomitantly
with
drugs
metabolised predominantly by
CYP3A4”
Unger M, et. al. Inhibition of cytochrome P450 3A4 by
extracts and kavalactones of Piper methysticum (KavaKava). Planta Med. 2002 Dec;68(12):1055-8
Kava-Kava inhibits CYP3A4
activity
“Since one case report described
the coma of a woman after
simultaneous ingestion of kava
and alprazolam, a substance
known to be metabolised by
CYP3A4, an in-vitro-in-vivo
correlation is obvious”
Unger M, et. al. Inhibition of cytochrome P450 3A4 by
extracts and kavalactones of Piper methysticum (KavaKava). Planta Med. 2002 Dec;68(12):1055-8
Licorice
Liquorice induces CYP activity
“While a single liquorice or glycyrrhizin
dose was unable to affect the
multienzymatic CYP-system, using both
schedules of repeated treatment, either
liquorice or glycyrrhizin were able to
significantly induce hepatic CYP3Aand, to a lesser extent, 2B1- and 1A2dependent microsomal monooxygenase
activities”
Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYPdependent monooxygenases. Life Sci. 1998; 62(6): 571-82
Liquorice induces CYP activity
“These results suggest that the induction
of
cytochrome
P450-dependent
activities by the prolonged intake of high
liquorice or glycyrrhizin doses, may
result in accelerated metabolism of
coadministered drugs with important
implications for their disposition”
Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYPdependent monooxygenases. Life Sci 1998; 62(6): 571-82
Echinacea
ECHINACEA: HERB-DRUG
INTERACTION
“Echinacea selectively modulates the
catalytic activity of CYP3A at hepatic
and intestinal sites. Caution should be
used when Echinacea is coadministered
with drugs dependent on CYP3A or
CYP1A2 for their elimination”
Gorski, JC. et al. The effect of Echinacea (Echinacea purpurea root) on
cytochrome P450 avtivity in vivo. Clin Pharmacol Ther 2004; 75: 89100
Echinacea Herb - Drug
Interaction
Echinacea dosing significantly reduced
the oral clearance of the CYP1A2 probe
caffeine by 27%
There is considerable interindividual
variability in this interaction, with 2
individuals showing a greater than 50%
reduction in oral clearance.
Gorski JC. Et al. The effect of Echinacea (Echinacea purpurea root) on
cyochrome P450 activity in vivo
Heavy Metals
METHYL MERCURY IS TOXIC
TO BOTH FOETAL AND ADULT
BRAINS
“The neurotoxic effects of methylmercury
(meHg) have been demonstrated in
both human and animal studies. Both
adult and foetal brains are susceptible
to the effects of meHg toxicity.”
Yokoo, E. et al Low level methylmercury exposure affects
neuropsychological function in adults. Environmental Health: A Global
Access Science Source 2003;2:8: 1-11
METHYLMERCURY
EXPOSURE AFFECTS MENTAL
FUNCTION
“adults exposed to meHg may be at risk for
deficits in neurocognitive function. The
functions disrupted in adults, namely
attention, fine motor function and verbal
memory, are similar….reported in children
with prenatal exposures”
Yokoo, E. et al Low level methylmercury exposure affects neuropsychological
function in adults. Environmental Health: A Global Access Science Source
2003; 2:8: 1-11
NICKEL IS A MAJOR
ENVIRONMENTAL TOXIN
“Nickel, a major environmental pollutant,
is known for its clastogenic, toxic and
carcinogenic potentials.
Ahmed S. et al. Ellagic acid ameliorates nickel induced biochemical
alterations: diminution of oxidative stress. Hum Exp Toxicol. 1999
Nov;18(11):691-8
Part Two
Improving
Biotransformation
Endogenous Toxins: Gut
Toxicity
The Human Gut has the
Largest Antigenic Load
Over the course of a lifetime, the
gastrointestinal tract processes more
than 25 tons of food, which represents
the largest load of antigens and
xenobiotics confronting the human
body.
Liska D. The detoxification enzyme systems. Alternative Medicine Review
1998;3(3):187-198
INTESTINAL HEALTH
OPTIMISES DETOXIFICATION
“about 25% of detoxification and removal
of toxins occurs in the intestine, which is
significant not only in the amount of
activity but also because once toxins
are deactivated in the intestines they
never enter the body.”
Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct
2002
The Gut is a
Biotransformational System
The GIT is the second major site in the
body for detoxification. Detoxification
enzymes such as Cyp3A4 and the
antiporter activities have been found in
high concentrations at the tip of the villi
in the intestine.
Adequate first pass metabolism of
xenobiotics by the GIT requires gut
mucosa integrity
Liska D. The detoxification enzyme systems. Alternative Medicine Review 1998;3(3):187-
Intestinal Permeability
Increases Xenobiotic Load
Compromised barrier function of the
mucosa will easily allow xenobiotic to
transit into the circulation without
opportunity for detoxification.
Liska D. The detoxification enzyme systems. Alternative Medicine Review
1998;3(3):187-198
Intestinal permeability increases
endotoxin exposure
A potential consequence of increased intestinal
permeability is microbial translocation.
Bacteria, fungi, and their toxins may
translocate across the mucosal barrier into
the
bloodstream
and
cause
sepsis.
Conditions that might benefit from glutamine
supplementation include food allergies and
associated conditions, Crohn’s disease,
ulcerative colitis and IBS.
Monograph: Glutamine. Alternative medicine review. 2001;6(4)
Anti-microbials
Berberis is a potent antimicrobial
Berberine extracts and decoctions have
demonstrated significant antimicrobial activity
against a variety of organisms including
bacteria,
viruses,
fungi,
protozoans,
Helminths, and Chlamydia. Currently, the
predominant clinical uses of berberine include
bacterial
diarrhoea,
intestinal
parasite
infections, and ocular trachoma infections.
Berberine. Altern Med Rev 2000;5(2):175-7
Berberine
Spares glutathione and induces a high
level of DNA repair synthesis.
Powerful hepatoprotective
Hwang JM. Inhibitory effect of berberine on tert-butyl hydroperoxide
induced
oxidative
damage
in
rat
liver.
ArchToxicol2002
Nov;76(11):664-70.
Reduces hepatic damage.
Janbaz KH.Studies on preventive and curative effects of berberine on
chemical induced hepatotoxicity in rodents. Fitoterapia. 2000Feb;
71(1):25-33
Protects against chemical carcinogenesis
Anis KV.Inhibition of chemicalcarcinogenesis by berberine in rats and
mice. J Pharm Pharmacol. 2001 May;53(5):763-8
Chinese wormwood is
antiparasitic
Artemisinin and its derivatives are a potent new
class of antimalarials, originated from
Artemisia annua, L. The clinical efficacy of
these drugs is characterised by an almost
immediate onset and rapid reduction of
parasitaemia. Their efficacy is high in such
areas as well where multidrug-resistance is
rampant.
Balint GA. Artemisinin and its derivatives: an important new class of
antimalarial agents. Pharmacol Ther 2001;90(2-3):261-
Grapefruit-seed is antimicrobial
Recent testimonials report grapefruit-seed extract to be
effective against more than 800 bacterial and viral
strains, 100 strains of fungus, and a large number of
single and multicelled parasites.
CONCLUSIONS: The initial data shows grapefruit-seed
extract to have antimicrobial properties against a
wide range of gram-negative and gram-positive
organisms at dilutions found to be safe.
Heggers JP, et. al. The effectiveness of processed grapefruit-seed extract
as an antibacterial agent: II. Mechanism of action and in vitro toxicity J
Altern Complement Med 2002;8(3):333-40
Colostrum protects against gut
pathogens
“Oligosaccharides and glycoconjugates are
some of the most important bioactive
components in milk.
Their primary role
seems to be in providing protection against
pathogens by acting as competitive inhibitors
for the binding sites on the epithelial surfaces
of the intestine. Evidence is also available to
support the role of some of these
components as growth promoters for genera
of beneficial microflora of the colon.”
Gopal PK, Gill HS. Oligosaccharides and glycoconjugates in bovine milk and
colostrum. Br J Nutr 2000:84(Suppl 1):S69-74
Colostrum Prevents
Endotoxinaemia
“Prophylactic pre-operative oral colostrum
shows significantly lower levels of endotoxin
and
endotoxin
neutralising
capacity
compared to placebo.
This suggests a
stabilisation of gut barrier during abdominal
surgery.”
Bolke E, et al Preoperative oral application of immunoglobulin-enriched colostrum
milk and mediator response during abdominal surgery. Shock. 2002 Jan;17(1):912.
Colostrum Neutralises
Bacterial Toxins
“An immunoglobulin preparation for oral use
was prepared from pooled bovine
colostrum: high antibacterial antibody
titres, a high capacity for the neutralisation
of bacterial toxins, well tolerated, highly
effective in the treatment of severe
diarrhoea.”
Stephan W, Dichtelmuller H, Lissner R. Antibodies from colostrum in oral
immunotherapy. J Clin Chem Clin Biochem. 1990 Jan;28(1):19-23
Colostrum Protects Gut
Mucosa
“We examined whether colostrum could reduce
the rise in gut permeability caused by
NSAIDs in volunteers and patients taking
NSAIDs for clinical reasons. In volunteers,
indomethacin caused a 3-fold increase in gut
permeability in the control arm, whereas no
significant increase in permeability was seen
when colostrum was co-administered.”
Playford RJ, et. al. Co-administration of the health food supplement,
bovine colostrum, reduces the acute non-steroidal anti-inflammatory
drug-induced increase in intestinal permeability. Clin Sci (Lond). 2001
Jun;100(6):627-33.
Colostrum Is Effective in
Refractory Diarrhoea
25 patients infected with the human
immunodeficiency virus with chronic
refractory
diarrhoea
and
either
confirmed cryptosporidiosis or absence
of demonstrable pathogenic organisms
were treated with a daily oral dose of 10
g of an immunoglobulin preparation
from bovine colostrum over a period of
10 days.
Colostrum is Effective in
Refractory Diarrhoea
Treatment of refractory diarrhoea with
immunoglobulins
from
bovine
colostrum constitutes an important
therapeutic approach and led to
complete (40%) or partial (24%)
remission of diarrhoea in 64% of the
patients described here.
Plettenberg A, et. al. A preparation from bovine colostrum in the treatment
of HIV-positive patients with chronic diarrhoea. Clin Investig. 1993
Jan;71(1):42-5
Probiotics
PROBIOTICS IMPROVE GUT
DETOXIFICATION
“The cells of lactic acid bacteria bind the
various fried-food mutagens and
remove them from the intestine”
Rao CV, et. al. Prevention of colonic preneoplastic lesions by the probiotic
Lactobacillus acidophilus NCFM in F344 rats. Int J Oncology
1999;14:939-44
“The NCFM strain of acidophilus adheres to Caco-2 and mucussecreting HT-29 cell culture systems, produces antimicrobial
compounds… NCFM survives gastrointestinal tract transit in
both healthy and diseased populations. NCFM inhibits aberrant
crypt formation in mutagenised rats, indicative of activity that
could decrease the risk of colon cancer. A blend of probiotic
strains containing NCFM decreased the incidence of pediatric
diarrhoea. NCFM led to a significant decrease in levels of toxic
amines in the blood of dialysis patients with small bowel
bacterial over-growth. NCFM may facilitate lactose digestion in
lactose-intolerant subjects.”
J Dairy Sci 2001;84:319-331
L. ACIDOPHILUS IMPROVES
GUT BIOTRANSFORMATION
“L. acidophilus have been shown to reduce
the counts of colonic putrefactive bacteria
as indicated by faecal bacterial βglucuronidase which is believed to be
largely responsible for the hydrolysis of
glucuronide conjugates in the colon and
thus important in the generation of toxic
and putative carcinogenic agents.”
Rao CV, et. al. Prevention of colonic preneoplastic lesions by the probiotic
Lactobacillus acidophilus NCFM in F344 rats. Int J Oncology 1999;14:939-44
LBA LOWERS SYSTEMIC
ENDOTOXIN LEVELS
“we found that giving oral LBA could reduce
the blood level of dimethylamine by about
31%, nitrosodimethylamine by 53% and
improve nutritional status as measured by
modest increases in weight gain, caloric
intake and anthropometric measurements”
Dunn S. Effect of oral administration of freeze-dried Lactobacillus acidophilus
on small bowel bacterial overgrowth in patients with end stage kidney
disease: reducing uraemic toxins and improving nutrition. Int Dairy J
1998;8:545-53
L. acidophilus Reduces Large
Bowel Tumour Promoters
Addition of L. acidophilus supplements to the
diet
reduces
β-glucuronidase
and
nitroreductase in rats and humans.
These interstitial alterations appear to reduce
the capacity of the intestinal flora to catalyse
the formation of carcinogens and / or the
promotional factors involved in the chemical
induction of large bowel tumours.
Goldin BR. The Effect of oral administration on Lactobacillus and
antibiotics on intestinal bacterial activity and chemical induction of large
bowel tumours. Symposium: genetics, physiology and utility of
Lactobacilli
Probiotics Reduce Atopic
Disease
Probiotics provide a non-pathogenic challenge
to the Th1 immune system, which has an
inhibitory effect on atopy.
Probiotics have also been shown to reverse
increased intestinal permeability and to
reduce antigen load in the gut by degrading
and
modifying
potentially
harmful
macromolecules.
Kalliomaki M, et al. Pandemic of atopic diseases - a lack of microbial exposure
in early infancy. Curr Drug Targets Infect Disord 2002 Sep;2(3):193-9
L. acidophilus induces Th1
immune cytokines
“A significant induction of IL-2 and IL-12
was observed with L. acidophilus.
These effects were dose dependent.”
Thus acidophilus induces Th1 cells via
the induction of IL-12 and IL-2.
Perdigon G, et. al. Interaction of lactic acid bacteria with the gut immune
system. Eur J Clin Nutr 2002;56:S21-6
Acidophilus prevents Th2 skewing
after antibiotic therapy
“These results suggest that adequate
probiotic intervention after antibiotic
treatment may improve the intestinal
ecosystem, and thereby prevent the
Th2-shifted immunity induced by
neonatal antibiotic use.”
Sudo N et al. An oral introduction of intestinal bacteria prevents the
development of a long-term Th2-skewed immunological memory
induced by neonatal antibiotic treatment in mice. Clin Exp Allergy
2002;32(7):1112-6
Probiotics Normalise Th1/Th2 by:
- normalising intestinal permeability
- balancing gut microecology,
- improving immunological defence barrier (IgA) of the
intestine,
- alleviating intestinal inflammation
- down regulation of proinflammatory cytokines
characteristic of local and systemic allergic
inflammation.
Miraglia del Giudice M et al. Probiotics and atopic dermatitis. A new strategy in atopic dermatitis. Dig Liver
Dis 2002;34:S68-71
Probiotics
L. plantarum 299v Improves
Immune Control
The strain L. plantarum 299v originates
from the human intestinal mucosa and
has been shown to decrease bacterial
translocation, improve mucosal status,
improve liver status, improve the
immunologic status of the mucosa, and
reduce mucosal inflammation.
Molin G. Probiotics in foods not containing milk or milk constituents, with
special reference to Lactobacillus plantarum 299v. Am J Clin Nutr 2001
Feb;73(2 Suppl):380S-385S
L. plantarum 299v Helps
Healing of the Gut
“In our study, administration of L. plantarum 299v seems
to reduce the inflammatory reaction and increase the
deposition of collagen at the healing wound, and thus
help to restore the continuity and healing of the
anastomotic part. Thus administration of lactobacilli
may modulate intestinal injury following radiation and
have some impact on cytoprotection.”
Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation
on colon anastomotic healing in an experimental model. Colorectal Disease
2001;3(4):245
L. plantarum 299V reduces Ulcerative
colitis in unresponsive patients
Nineteen patients with ulcerative colitis who had
remained unresponsive to 4 weeks of treatment
with corticosteroid and 5-aminosalyclic acid
therapy received L. plantarum 299v or placebo.
Seven of the 10 patients who received 299v
solution achieved clinical and colonoscopic
remission. One had a partial response and two
failed to respond at all. In the placebo group (n =
9), no patient achieved remission and only two
had a partial improvement.
Kordecki H, Niedzielin K: New conception in the treatment of ulcerative colitis: Probiotics as a
modification of the microflora of the colon (Abstr). IN Proceedings of Falk Symposium No. 105,
1998, 45
L. plantarum 299v Improves
IBS
Forty patients were trialled in a controlled,
double-blind randomised study to assess the
effect of 299v on IBS. They received either
Lactobacillus plantarum 299v (20 patients) or
placebo (20 patients) over a period of 4 weeks.
RESULTS: “All patients treated with Lactobacillus
plantarum 299V reported resolution of their
abdominal pain.”
Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomised study on
the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel
syndrome. Eur J Gastroenterol Hepatol 2001 Oct;13(10):1143-7
% of patients with improvment
Treatment Outcome of IBS Patients with
L plantarum (299v) over 4 Weeks
120
100
80
100%
60
95%
40
20
55%
Placebo
L.plantarum
60%
18%
15%
0
Abdominal
Pain
Stool
Frequency
IBS
Symptoms
Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of
Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol
2001 Oct;13(10):1143-7
L. Plantarum 299v Reduces
Cardiovascular Risk Factors
Studies show in hypercholesterolaemic patients
that supplementation with the probiotic bacteria
Lactobacillus plantarum 299v significantly
lowers concentrations of LDL cholesterol and
fibrinogen. The short-chain fatty acids formed in
the human colon by the bacterial fermentation of
fibre may have an anti-inflammatory effect, may
reduce insulin production, and may improve lipid
metabolism.
Naruszewicz M, et al. Effect of lactobacillus plantarum 299v on cardiovascular
disease risk factors in smokers. Am J Clin Nutr 2002;76(6):1249-55
L. plantarum Reduces
Cardiovascular Risk Factors in
smokers within 6 weeks of treatment
LDL Cholesterol
Leptin
Fibrinogen
BP
L.plantarum
(299v)
Isoprostanes
IL-6
Monocyte
Adhesion
Naruszewicz M et al. Effect of L.plantarum 299v on Cardiovascular disease risk
factors in smokers Am J Clin Nutr 2002;76(6):1249-55
Glutamine Reduces Gut
Inflammation
“Glutamine reduces pro-inflammatory
cytokine production by human intestinal
mucosa,
probably
by
a
posttranscriptional
pathway.
Glutamine
could
be
useful
to
modulate
inflammatory
conditions
with
imbalanced cytokine production.”
Coeffier M, et. al. Influence of glutamine on cytokine production by human
gut in vitro. Cytokine 2001;13(3):148-54
Glutamine Maintains Gut Health
“Glutamine
and
glutamine
supplementation appear to be important
for the normal maintenance of intestinal
morphology and function, intestinal
adaptation following resection, and
prevention of clinical infection related to
bacterial translocation.”
Buchman AL. Glutamine for the gut: mystical properties or an ordinary
amino acid? Curr Gastroenterol Rep 1999 Oct;1(5):417-23
Effects of Glutamine
• Glutamine Reduces Gut Inflammation
• Glutamine Maintains Gut Health
• Glutamine Improves Gut Function
Licorice
Deglycyrrhizinated liquorice
protects gastric mucosa
Gastric mucosal damage induced by oral
administration of 60mg of aspirin is reduced
by simultaneous administration of 100-500mg
deglycyrrhizinated liquorice. Human faecal
blood loss induced by 975mg aspirin three
times a day, was less when 350mg of
deglycyrrhizinated liquorice was administered
with each dose of aspirin.
Rees WD, et. al. Effect of deglycyrrhizinated liquorice on gastric
mucosal damage by aspirin. Scand J Gastroenterol 1979;14(5):6057.
Deglycyrrhizinated liquorice
effective for gastric ulcers
In a trial of DGL for the treatment of peptic
ulcer, it was found to be as effective as
cimetidine (Tagamet).
Morgan AG, et. al. Comparison between cimetidine and Caved-S in the
treatment of gastric ulceration, and subsequent maintenance therapy.
Gut 1982;23:545-551.
Another trial published in the Lancet the
same year found DGL to be as effective
as ranitidine (Zantac).
Glick L. Deglycyrrhizinated liquorice for peptic ulcer. Lancet 1982;9:817.
Aloe vera a powerful antiinflammatory
“Aloe vera was active in all models of
inflammation. Oral activity of Aloe vera
was demonstrated to be dependent on
the presence of anthraquinones. The
various irritant-induced oedema models
provided a broad spectrum of antiinflammatory activity for Aloe vera
Davis RH, et. al. Anti-inflammatory activity of Aloe vera against a
spectrum of irritants. J Am Podiatr Med Assoc. 1989;79(6):263-276
Aloe is a safe and effective
laxative
“Aloe is a potent laxative due to its
anthraquinone glycosides content which
act directly on the lining of the intestines
to stimulate peristalsis and which
increase water absorption in the
intestines”
Roberts AJ, et. al. Nutraceuticals: the Complete Encyclopedia of
Supplements, Herbs, Vitamins and Healing Foods. Berkely Publishing
Group. New York, USA. 2001:93
Liver Detoxification
macronutrients
PROTEIN REQUIRED FOR
DETOXIFICATION
“Hepatic mixed-function oxidase activities
increase with increase in dietary proteins. In
rodents fed with high protein diet, acute oral
toxicity of a number of pesticides (lindane,
malathione, DDT, carbaryl and captan) have
been shown to be reduced.”
“Oxidative drug metabolism (phase I reactions)
of antipyrine, theophylline, propranolol and
other drugs in humans is increased with
protein rich diet.”
PROTEIN CONSUMPTION
SUPPORTS PHASE II
“High quality protein is a good source of
methionine, cysteine, glutamine and
glycine in a form that provides high
absorption; these amino acids can be
used to generate sulphation, glutathione
and amino acid conjugation cofactors.”
Liska D, et. al. From the Townsend Letter for Doctors and Patients. Oct
2002
PHASE II INDUCTION
ELEVATES GLUTATHIONE
“The induction of these (phase II)
enzymes is accompanied by elevations
of intracellular GSH levels which
augment cellular antioxidant protection”
Prestera T. Chemical and molecular regulation of enzymes that detoxify
carcinogen. Proc Natl Acad. Sci 1993;90:2965-69
ADEQUATE PHASE II ACTIVITY
PROMOTES EFFECTIVE
BIOTRANSFORMATION
“In general, increases in phase I combined with
increases in phase II metabolism will result in
faster clearance and reduced carcinogenicity of
ingested procarcinogens such as polycyclic
hydrocarbons”
Ronis M. Altered expression and glucocorticoid-inducibility of hepatic CYP3A and
CYP2B enzymes in male rats fed diets containing soy protein isolate. J Nutr
1999;129:1958-65
IMPORTANCE OF PHASE II
INDUCERS
“a voluminous literature now supports the
view that induction of phase II enzymes
is
an
important
and
sufficient
mechanism for achieving protection
against the toxic and neoplastic effects
of many carcinogens”
Talalay P, et. al. Phytochemicals from cruciferous plants protect against
cancer by modulating carcinogen metabolism.
J Nutr
2001;131(S):3027S-33S
Silymarin
SILYMARIN AS A
HEPATOPROTECTANT
“Milk thistle is commonly used as a
hepatoprotectant. Silymarin, the major
component of milk thistle, is reported to
inhibit nitric oxide production, is a potent
free radical scavenger and prevents
lipid peroxidation,”
Venkataramanan, et. al. Milk thistle, a herbal supplement,
decreases the activity of CYP 3A4 and uridine
diphosphoglucuronosyl transferase in human hepatocyte
cultures. Drug Metabolism and Disposition 2000;28(11):127073
SILYMARIN AS A
HEPATOPROTECTANT
“Silymarin enhances the activity of
hepatocyte RNA polymerase, and
complexes
toxic
free
iron.
Silymarin/silybin is reported to protect
the liver against several hepatotoxins in
rats.”
Venkataramanan, et. al. Milk thistle, a herbal supplement,
decreases the activity of CYP 3A4 and uridine
diphosphoglucuronosyl transferase in human hepatocyte
cultures. Drug Metabolism and Disposition 2000;28(11):127073
SILYMARIN REDUCES CYP3A4
“Treatment with silymarin (0.1 and 0.25
mM) significantly reduced the activity of
CYP 3A4 enzyme (by 50 and 100%,
respectively)”
Venkataramanan, et. al. Milk thistle, a herbal supplement, decreases the
activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in
human hepatocyte cultures. Drug Metabolism and Disposition
2000;28(11):1270-73
SILYMARIN MODULATES
BIOTRANSFORMATION
“Our studies clearly document the
potential of silymarin to inhibit the
metabolism of substrates of CYP 3A4
and UGT1A6/9 in humans.”
Venkataramanan, et. al. Milk thistle, a herbal supplement, decreases the
activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in
human hepatocyte cultures. Drug Metabolism and Disposition
2000;28(11):1270-73
Silybum increases hepatic
glutathione
Silybum has also received attention for its
ability to increase the intracellular
concentration of glutathione in the liver
and prevent cellular damage by toxins.
Scanlan N. Compromised hepatic detoxification in companion
animals and it’s correction via nutritional supplementation and
modified fasting. Alternative Medicine Review.
2001;6(suppl)s24-s37.
Silymarin improves alcoholic
liver disease
“histological findings were reported as
improved in two out of two trials,
improvement of prothrombin time was
significant (two trials pooled) and liver
transaminase levels were consistently
lower in the silymarin-treated groups.
Therefore, silymarin may be of use as an
adjuvant in the therapy of alcoholic liver
disease”
Saller R, et. al. The use of silymarin in the treatment of liver diseases.
Drugs. 2001; 61(14):2035-63
BIFUNCTIONAL EFFECTS OF
SILYMARIN
•
•
•
•
•
•
Inhibits phase I enzymes (CYP3A4)
Increases glutathione peroxidase
Induces glutathione transferase
Increases serum glutathione
Improve liver function in toxic exposure
Strong antioxidant activity
Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct
2002
Glycine
GLYCINE ATTENUATES
TOXIN-INDUCED HEPATIC
INJURY
“Destruction of Kupffer cells with
gadolinium chloride as well as Kupffer
cell inactivation with dietary glycine,
diminishes stellate cell α-smooth
muscle actin expression and collagen
production, most likely by preventing the
release of profibrogenic cytokines from
Kupffer cells.”
GLYCINE PREVENTS LIVER
DAMAGE
“In a rat model of endotoxin shock, dietary
supplementation with glycine blunted liver
and lung injury and improved survival.
Furthermore, dietary glycine prevented
necrosis and inflammation that developed
early during chronic intragastric ethanol
administration.”
Rivera C. et al. Attenuation of CCl4-induced hepatic fibrosis by GdCl3
treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol
2001;281:G200-7
GLYCINE PREVENTS LIVER
DAMAGE
“glycine may be an effective therapy
against liver damage, including injury
caused by chronic exposure to alcohol.
The mechanism of protection against
injury afforded by glycine most likely
involves the inactivation of Kupffer
cells.”
Rivera C. et al. Attenuation of CCl4-induced hepatic fibrosis by GdCl3
treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol
2001; 281:G200-7
Glycine conjugation is
dependent on glycine supply
“It is concluded that the activity of
glycine cleavage system is an
important determinant of glycine
supply and, thereby, the capacity of
glycine conjugation of xenobiotics”
Gregus Z, et. al. Dependence of glycine conjugation on availability
of glycine: role of the glycine cleavage system. Xenobiotica. 1993
Feb; 23(2): 141-53
Glycine conjugation is
dependent on glycine supply
“The normal endogenous glycine
supply permits glycine conjugation
only at an approximate halfmaximal rate”
Gregus Z, et. al. Dependence of glycine conjugation on
availability of glycine: role of the glycine cleavage system.
Xenobiotica. 1993 Feb; 23(2): 141-53
Glycine reduces hepatic injury
“Importantly, dietary glycine (5%) largely
blocked chronic CsA-induced activation of
Kupffer cells, blunted production of PGE(2),
prevented the hypermetabolic state, and
minimised tissue hypoxia”
Zhong Z, et. al. Cyclosporin A causes a hypermetabolic state and hypoxia in
the liver: prevention by dietary glycine. J Pharmacol Exp Ther. 2001 Dec;
299(3): 858-65
Glycine attenuates hepatic
injury
“Dietary glycine is protective in rat models
against endotoxemia, liver ischemiareperfusion, and liver transplantation,
most likely by inactivating the Kupffer
cell via this newly identified glycinegated chloride channel”
Wheeler MD, et. al. Glycine: a new anti-inflammatory immunonutrient. Cell
Mol Life Sci. 1999 Nov 30;56(9-10):843-56.
Glycine attenuates hepatic
injury
“Moreover, dietary glycine is protective in
the kidney against cyclosporin A toxicity
and ischemia-reperfusion injury. Glycine
may be useful clinically for the treatment
of sepsis, adult respiratory distress
syndrome, arthritis, and other diseases
with an inflammatory component”
Wheeler MD, et. al. Glycine: a new anti-inflammatory immunonutrient. Cell
Mol Life Sci. 1999 Nov 30;56(9-10):843-56.
Calcium-D-Glucarate
CALCIUM-D-GLUCARATE
INHIBITS BETAGLUCURONIDASE
“Supplementation of calcium-D-glucarate
has been shown to inhibit betaglucuronidase, an enzyme produced by
colonic microflora and involved in phase
II liver detoxification.”
Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug
CALCIUM-D-GLUCARATE
IMPROVES OESTROGEN
DETOXIFICATION
“Calcium-D-glucarate’s inhibition of betaglucuronidase activity allows the body to
excrete hormones such as oestrogen
before they can become reabsorbed.”
Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug
CALCIUM-D-GLUCARATE
INCREASES
GLUCURONIDATION
“Calcium-d-glucarate’s detoxifying and
anticarcinogenic
properties
are
attributed to its ability to increase
glucuronidation
and
excretion of
potentially toxic compounds.”
Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug
CALCIUM-D-GLUCARATE
IMPROVES OESTROGEN
DETOXIFICATION
“Because many breast cancers are
oestrogen-dependent,
calcium-Dglucarate’s ability to affect oestrogen
and other hormone levels has led to
Phase I clinical trials at several major
cancer centres in the U.S.”
Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug
GLUCURONIDATION
• Chemical carcinogens
• Steroid hormones
• Lipid-soluble toxins
During phase II detoxification, these
toxins are conjugated with glucuronic
acid in the liver (glucuronidation), and
excreted through the biliary tract.
Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug
PHYTONUTRIENTS Regulate
Phase 1 Detox
“They have the capacity to inhibit certain
enzymes (CYP) at high concentrations
of the compound and to activate
moderately the same enzyme at lower
concentrations”
Lampe J. Health effects of vegetables and fruit: assessing mechanisms of
action in human experimental studies.
Am J Clin Nutr
1999;70(suppl):475S-490S
PHYTONUTRIENTS Regulate
Phase 1 Detox
“This points to a complex association
between consumption of a typical diet of
various
vegetables
and
biotransformation enzyme activities in
humans”
Lampe J. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P4501A2 activity in humans: changes to caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000;21(6):1157-62
Increasing Phase 2 Improves
Detoxification
Commonly, the glutathione S-transferase and
glucuronyl transferases are induced by bifunctional inducers.
In general, this increase in Phase II supports
better detoxification in the individual and
helps to promote and maintain a healthy
balance between Phase I and Phase II
activities.
Liska D. The Detoxification Enzyme Systems. Alternative Medicine Review.
1998;3(3): 187-198
Bi-functional support improves
detoxification and symptoms
In organisms where Phase I enzymes are high
but Phase II enzymes are low, there is a
great risk of a toxic episode.
Scanlan N. Compromised hepatic detoxification in companion animals and
it’s correction via nutritional supplementation and modified fasting.
Alternative Medicine Review. 2001;Vol6(suppl):S24-S37.
Cruciferous vegetables reduce
cancer risk
The unique effectiveness of cruciferous
vegetables to protect against neoplastic
disease is attributed to the fact that they
are the richest sources of glucosinolates
in the human diet.
Brassica species can contain a dozen
different glucosinolates… a lower-risk
enzyme profile
Lampe J, Peterson S. Brassica, biotransformation and cancer risk:
Genetic polymorphisms alter the preventive effects of cruciferous
vegetables. American society for nutritional sciences, June 2002.
CRUCIFEROUS VEGETABLES
ARE BIFUNCTIONAL
MODULATORS
“For example, compounds in cruciferous
vegetables can alter drug metabolism
by both inhibiting and inducing certain
CYP’s and possibly by inducing select
conjugating enzymes.”
Lampe J. Health effects of vegetables and fruit: assessing mechanisms of
action in human experimental studies.
Am J Clin Nutr
1999;70(suppl):475S-490S
BROCCOLI AND
WATERCRESS INHIBIT
CYP3A4
“The inhibition (of) CYP3A4 (by PEITC)
was a mixed type of competitive and
non-competitive inhibition”
Nakajima M. Inhibition and inactivation of human cytochrome P450
isoforms by phenethyl isothiocyanate.
Drug Metabolism and
Disposition 2001;29(8):1110-13
SULFORAPHANE: THE MOST
POTENT PHASE II INDUCER
“Sulforaphane is an extremely potent
inducer of phase II enzymes, perhaps
the most potent naturally occurring
inducer described to date.”
Talalay P et al. Phytochemicals from cruciferous plants protect against
cancer by modulating carcinogen metabolism.
J Nutr
2001;131(S):3027S-33S
Glucosinolates are Converted
to Isothiocyonates
“Crucifers that are widely consumed are
especially rich in glucosinolates, which
are converted by plant myrosinase and
gastrointestinal
microflora
to
isothiocyanates”
Talalay P et al. Phytochemicals from cruciferous plants protect against
cancer by modulating carcinogen metabolism.
J Nutr
2001;131(S):3027S-33S
SULFORAPHANE
OVERCOMES ANTIBIOTIC
RESISTANCE
“H. pylori is now recognised as one of the
most prevalent human pathogens in the
world...it is difficult to eradicate in 15-20% of
individuals by antibiotic therapy, which is
now recommended for infected patients with
gastric or duodenal ulcers or gastric
mucosa-associated
lymphoid
tissue
lymphoma”
Fahey, J. Sulforophane inhibits extracellular, intracelllular, and antibiotic resistant
strains of helicobacter pylori and prevents benzo(a)pyrene-induced stomach
tumours. PNAS 2002 May;99(11):7610-15
SULFORAPHANE
OVERCOMES ANTIBIOTIC
RESISTANCE
“sulforaphane.. an isothiocyanate abundant
as its glucosinolate precursor in certain
varieties of broccoli and broccoli sprouts, is
a potent bacteriostatic agent against 3
reference strains and 45 clinical isolates of
H. pylori, irrespective of their resistance to
conventional antibiotics.
Fahey, J. Sulforophane inhibits extracellular, intracelllular, and antibiotic
resistant strains of helicobacter pylori and prevents benzo(a)pyrene-induced
stomach tumours. PNAS 2002 May;99(11):7610-15
Bi-functional effects of
Brassica Family
•
•
•
•
•
•
Decreases CYP3A4 activity
Up-regulates CYP1A2
Induces glutathione-S-transferase
Up-regulates glutathione
Induces quinone reductase
Induces glucuronidation
Effects of Sulforaphane
• Most potent phase II enzyme inducer
• Bacteriostatic
(H.
pylori,
other
pathogens)
• Induces glutathione-S-transferase
• Up-regulates glutathione
• Induces quinone reductase
• Induces glucuronidation
Watercress
WATERCRESS IMPROVES
BIOTRANSFORMATION
“Phenethyl isothiocyanate can inhibit
metabolism of 4-(methylnitrosamin)-1(3-pyridyl)-1-butanone
a
tobaccospecific lung carcinogen. …Watercress
consumption
increased
urinary
excretion of detoxified metabolites by
30%.”
Lampe J. Health effects of vegetables and fruit: assessing mechanisms of
action in human experimental studies. Am J Clin Nutr
1999;70(suppl):475S-490S
Watercress reduces DNA
damage
Treatment of Hep G2 cells with small amounts
of watercress or garden cress juice and
benzo(a)pyrene reduced the genotoxic effect
of the benzo(a)pyrene in a dose dependent
manner.
Findings show that garden and water cress
juices are highly protective against B(a)P induced DNA damage in human derived cells.
Kassie F. Effects of garden and water cress juices and their constituents,
benzyl and phenethyl isothiocyanates, towards benzo(a)pyreneinduced DNA damage: a model study with the single cell gel
electrophoresis / Hep G2 assay. Chemico-Biological Interactions
2003;142:285 - 296.
WATERCRESS INHIBITS
CYP2E1 ACTIVITY
“results show that a single ingestion of
watercress inhibits the hydroxylation of
chlorzoxazone, an in vivo probe for
CYP2E1 (in human volunteers)”
Leclercq I et al. Inhibition of chlorzoxazone metabolism, a clinical probe for
CYP2E1, by single ingestion of watercress. Clin Pharmacol Ther
1998;64(2):144-9
BIFUNCTIONAL EFFECTS OF
WATERCRESS
• Selective inhibition of phase I
• Induction of phase II glucuronosyl
transferases
• Induction
of
glutathione-Stransferases
Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct
2002
Green Tea
Green tea decreases CYP
activity
“Catechins also inhibited the oxidations of
typical substrates catalysed by human
CYPs, namely ethoxycoumarin Odeethylation by CYP1A1, ethoxyresorufin
O-deethylation
by
CYP1A2
and
midazolam 1'-hydroxylation by CYP3A4”
Muto S, et. al. Inhibition by green tea catechins of metabolic activation of
procarcinogens by human cytochrome P450. Mutat Res 2001;479(12):197-206
Green tea decreases CYP
activity
“Epicatechin gallate inhibited other
forms of human CYP such as CYP2A6,
CYP2C19 and CYP2E1, indicating the
non-specific
inhibitory
effects
of
epicatechin gallate toward human
CYPs”
Muto S, et. al. Inhibition by green tea catechins of metabolic activation
of procarcinogens by human cytochrome P450. Mutat Res 2001;479(12):197-206
Green tea maintains bowel
detoxification
The reduction of such faecal parameters
as moisture, pH, ammonia, sulphide,
and ORP by tea catechin administration
indicated very favourable improvements
of the subjects bowel conditions.
Goto K et al. The effects of tea catechins on faecal conditions of elderly
residents in a long term care facility.
J Nutr Sci Vitaminol
1999;45(1):135-41
Green Tea Induces Phase II
Activity
Induction of phase II enzymes, glutathione-Stransferase and quinone reductase, were
enhanced by nearly all tea fractions, while
glutathione was induced by only a few
fractions.
Steele VE. Comparative chemopreventative mechanisms of green tea, black tea and
selected polyphenol extracts measured by in vitro bioassays. Carcinogenesis
2000;21(1):63-67
Green Tea Reduces Cancer
Incidence
Cancers reduced by Green Tea consumption:
• breast
• colon and rectum
• gall bladder and liver
• lung and nasopharynx
• pancreas
• stomach
• uterus
Green Tea Inhibits Free
Radical Formation
Most tea fractions inhibited free radical
formation in human cells as measured
by nine in vitro assays.
Steele VE. Comparative chemopreventative mechanisms of green tea, black tea
and selected polyphenol extracts measured by in vitro bioassays.
Carcinogenesis 2000;21(1):63-67
BIFUNCTIONAL EFFECTS OF
CATECHINS
• Modulation of phase I detoxification
• Induction of phase II glucuronidation
• Enhance
glutathione
conjugation
enzymes
• Anticarcinogenic
• Antimutagenic
• Antioxidant
Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct
2002
Artichoke
Artichoke improves
detoxification
The artichoke extracts did not affect the
cellular level of glutathione (GSH) but
diminished the loss of total GSH and the
cellular leakage of GSS resulting from
exposure to tert-butylhydroperoxide.
Gebhardt R. Antioxidative and protective properties of extracts from leaves
of the articholke (Cynara scolymus L.) against hydroperoxide-induced
oxidative stress in cultured rat hepatocytes. Toxicol Appl Pharmacol
1997;144(2):279-86
Artichoke is a powerful
hepatoprotectant
These results demonstrate that artichoke
extracts have a marked antioxidative
and protective potential.
Gebhardt R. Antioxidative and protective properties of extracts from leaves
of the articholke ( Cynara scolymus L.) against hydroperoxide-induced
oxidative stress in cultured rat hepatocytes. Toxicol Appl Pharmacol
1997;144(2):279-86
Curcumin
Curcumin inhibits carcinogen
bioactivation
“Because CYP1A1 is one of the primary
carcinogen-activating enzymes in oral
mucosa, the use of curcumin as an oral
cavity chemopreventive agent could have
significant clinical impact via its ability to
inhibit carcinogen bioactivation”
Rinaldi, et. al. Curcumin activates the aryl hydrocarbon receptor yet
significantly inhibits (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation
in oral squamous cell carcinoma cells and oral mucosa. Cancer Res. 2002;
62(19):5451-6
Curcumin Blocks CarcinogenDNA Adducts
Curcumin
has
been
shown
in
experimental studies to have antiinflammatory properties, to prevent
tumourigenesis mutagenesis, to block
carcinogen - DNA adduct formation, and
to inhibit angiogenesis.
Dinkova-Kostova AT. Relation of structure of curcumin analogues to their
potencies as inducers of Phase 2 detoxification enzymes..
Carcinogenesis. 1999;20(5 ):911-914
Curcuminoids Induce Phase 2
Activity
Curcumin and a number of naturally
occurring and synthetic analogues are
phase 2 enzyme inducers, as
demonstrated by their ability to elevate
the enzyme activity of QR in hepatoma
cells. This plays a major role in its
chemoprotective
and
antioxidant
activities.
Dinkova-Kostova AT. Relation of structure of curcumin analogues to their
potencies as inducers of Phase 2 detoxification enzymes..
Carcinogenesis. 1999;20(5 ):911-914
Tumeric reduces endotoxic
hepatic injury
“These results demonstrate that
curcuminoids are effective in
suppressing the hepatic microvascular
inflammatory response to LPS and may
be a natural alternative antiinflammatory substance”
Lukita-Atmadja W, et. al. Effect of curcuminoids as anti-inflammatory
agents on the hepatic microvascular response to endotoxin. Shock.
2002 May;17(5):399-403.
Curcumin is a Bifunctional
Modulator
• Chemoprotective agent:
– elevates activity of phase 2 detoxification
enzymes of xenobiotic metabolism eg,
glutathione transferases and NAD(P)H:
quinone reductase.
– Inhibits procarcinogen activating Phase 1
enzymes eg, CYP4501A1.
Dinkova-Kostova AT. Relation of structure of curcumin analogues to their
potencies as inducers of Phase 2 detoxification enzymes..
Carcinogenesis. 1999;20(5 ):911-914
Limonene
Limonene improves functional
biotransformation
“The blocking chemopreventive effects of
limonene and other monoterpenes during
the initiation phase of mammary
carcinogenesis are likely due to the
induction of Phase I and Phase II
carcinogen-metabolizing
enzymes,
resulting in carcinogen detoxification”
Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J
Nutr 1999;129(3):775S-778S
Limonene improves functional
biotransformation
Ironically, a comparative analysis of DMBA
metabolism in control, limonene-treated rats
revealed that more of the proximate
carcinogen is produced in monoterpenetreated animals than in controls However,
these effects are overcome by the induction
of glutathione-S-transferase and UDPglucuronyl transferase by limonene”
Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J
Nutr. 1999 Mar;129(3):775S-778S
Limonene improves functional
biotransformation
“These results correlate well with the
reduction in tumour incidence and
multiplicity observed in rats treated with
dietary limonene during the initiation phase
of DMBA-induced mammary cancer”
Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J
Nutr 1999;129(3):775S-778S
Limonene improves
biotransformation
“Dietary D-limonene (1.0% diet for 10 days)
maintained liver GSH concentrations at
92% of control values in the paracetamolchallenged mouse without altering GST
activity. D-Limonene also increased liver
GSH concentration (23%) in mouse fed
1.0% D-limonene alone.”
Reicks MM. Effects of D-limonene on hepatic microsomal monooxygenase
activity and paracetamol-induced glutathione depletion in mouse. Xenobiotica.
1993;23(7):809-19
Limonene improves
biotransformation
“D-Limonene, a monoterpenoid constituent
of citrus fruit oil, blocks tumour induction by
chemical carcinogens in laboratory animals,
apparently by preventing bioactivation of
procarcinogens
and
by
enhancing
conjugation of proximal carcinogenic
metabolites.”
Reicks M. Effects of D-limonene on hepatic microsomal monooxygenase
activity and paracetamol-induced glutathione depletion in mouse. Xenobiotica.
1993;23(7):809-19
Limonene and breast cancer
“Monoterpenes are found in the essential oils
of many commonly consumed fruits and
vegetables. These compounds have been
shown to exert chemopreventive and
chemotherapeutic activities in mammary
tumour models and represent a new class of
breast cancer therapeutic agents”
Bardon S, et. al. Monoterpenes inhibit cell growth, cell cycle progression, and
cyclin D1 gene expression in human breast cancer cell lines. Nutr Cancer.
1998;32(1):1-7.
Limonene and breast cancer
We investigated the effects of limonene and
limonene-related monoterpenes on cell
growth, cell cycle progression, and
expression of cyclin D1 cell cycle-regulatory
gene in breast cancer cell lines. Our results
revealed
that
limonene-related
monoterpenes caused a dose-dependent
inhibition of cell proliferation.”
Bardon S, et. al. Monoterpenes inhibit cell growth, cell cycle progression, and
cyclin D1 gene expression in human breast cancer cell lines. Nutr Cancer.
1998;32(1):1-7.
APIACEOUS VEGETABLES
DECREASE CYP1A2
“CYP1A2 activity: Brassica vegetables
increased and apiaceous vegetables
decreased activity compared with the basal
and allium diets. This points to a complex
association between consumption of a
typical diet of various vegetables and
biotransformation enzyme activities in
humans”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets. Carcinogenesis
APIACEOUS VEGETABLES
REDUCE PHASE 1 ACTIVITY
“Some Rutaceae (eg. citrus fruits) also
contain furanocoumarins and inhibition
of CYP3A4 and CYP1A2 activity by
grapefruit juice has been attributed in
part
to
the
presence
of
furanocoumarins”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000; 21(6):1157-62
APIACEOUS FAMILY
DECREASES CYP ACTIVITY
“Certain apiaceous vegetables, including
celery, parsnips and parsley, are
significant sources of furanocoumarins,
compounds which have been shown to
inhibit several human P450s.”
Lampe J. et al. Brassica vegetables increase and apiaceous vegetables
decrease cytochrome P450 1A2 activity in humans: changes in caffeine
metabolite ratios in response to controlled vegetable diets.
Carcinogenesis 2000; 21(6):1157-62
BUPLEURUM IS ANTIINFLAMMATORY
“Bupleurum
falcatum
L.,
(containing)
saikosaponins a and d …. had metabolic
actions as well as anti-inflammatory actions.
These metabolic actions and antiinflammatory action of saikosaponins may
confirm
the
clinical
application
of
Bupleurum.”
Abe H et al. Protective effect of saikosaponin-d isolated from Bupleurum falcatum
L. on CCl4-induced liver injury in the rat. Naunyn Schmiedebergs Arch
Pharmacol. 1982 Sep;320(3):266-71
Bupleurum increases bile
production
Both aqueous and decoction of Bupleurum
have been shown to increase total bile
output and bile salt content, indicating
cholagogic and choleretic actions.
Chang, H, et. al. Pharmacology and application of Chinese materia medica,
Vol 2. World scientific publishing Co. 1987
Bupleurum increases bile
production
Oral administration of Bupleurum species
to dogs with carbon tetrachloride-induced
hepatitis quickly restored to normal the
deranged hepatobillary secretion function
and chemical composition of bile .
Chang, H, et. al. Pharmacology and application of Chinese materia medica,
Vol 2. World scientific publishing Co. 1987
BUPLEURUM REDUCES
HEPATIC INJURY
Pretreatment with saikosaponin-d produced a
remarkable inhibitory action on acute hepatic
injury by CCl4. A significant inhibition of lipid
peroxidation induced by an acute dose of CCl4 in
the liver of rats pre-treated with saikosaponin-d
was also noted”
Abe H et al. Protective effect of saikosaponin-d isolated from Bupleurum falcatum L. on
CCl4-induced liver injury in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1982
Sep;320(3):266-71
Bupleurum exerts anti-hepatitis B
activity
Saikosaponins, the main active constituents
of Bupleurum spp, have been shown to
possess
immunomodulatory,
hepatoprotective, anti-tumour and antiviral activities.
Results showed that HBV-transfected
human hepatoma cells, cultured with
saikosaponin c showed a significantly
lower level of HBeAg in culture medium.
Chiang LC, et al. Cytotoxicity and anti-hepatitis B virus activities of
saikosaponins from bupleurum species. Planta Med 2003;69:705709
Barberry
Berberine stimulates bile
secretion
“Berberine is an alkaoloid found in a number of
clinically-important medicinal plants, including
Berberis vulgaris (barberry). Berberines
actions include the ablility to stimulate bile
secretion and billirubin discharge.”
The activity of berberine may explain the long
traditional use of berberis as a cholagouge in
the treatment of hepatic disorders.
Bidsall, T, et. al. Berberine: theraputic potential of an alkaloid found in several
medicinal plants. Alt Med Rev. 1997;2(2):94-103
Taurine
Bile synthesis requires taurine
For bile acids to be solubilised at
physiological pH, it is essential they be
conjugated through peptide linkages
with either glycine or taurine.
Taurine conjugation of bile acids has a
significant effect on the solubility of
cholesterol, increasing it’s excretion and
reducing serum levels.
Mizushima S. et al. Effects of oral taurine supplementation on lipids and
sympathetic nerve tone. Adv Exp Med Biol 1996;403:615-622
Taurine accelerates bile
synthesis
The total bile acids concentration in the feces
and intestinal contents of rats fed taurine
were significantly higher than those in rats fed
a control diet.
Taurine accelerated bile acid synthesis and
excretion, thereby increasing cholesterol
consumption
Kishida T, et al. Increase of bile acids synthesis and excretion caused by taurine
administration prevents the ovariectomy-induced increase in cholesterol
concentrations in the serum low-density lipoprotein fraction of Wistar rats. J
Nutr Biochem. 2003 Jan;14(1):7-16.
Taurine is the preferred bile
substrate
Taurine-conjugated bile acids are more
water-soluble and less toxic than glycoconjugated bile acids.
Bellentani S, et al. Taurine increases bile acid pool size and reduces bile
saturation index in the hamster. J Lipid Research 1997;28:1021-1027.
Taurine scavenges free
radicals
Taurine is able to attenuate DNA damage
caused by aromatic amine compounds.
Taurine is an antioxidant that specifically
mediates the chloride ion and hypochlorous
acid concentration, and protects the body
from potentially toxic effects of aldehyde
release.
Kozumbo WJ, Et al. Breakage and binding of DNA by reaction products of
hypochlorous acid with aniline, l-naphthlamine or l-naphthol. Toxicol Appl
Pharmacol 1992;115:107-115.
Taurine protects against
endotoxins
In experimental animals, taurine was
found to significantly inhibit intestinal
translocation and to protect the animals
from endotoxaemic injury.
Wang WY. Intestinal endotoxin translocation in endotoxemic rats. Sheng Li
Ko Hsueh Chin Chan 1995;26:41-44.
Glutathione
Oral glutathione increases
tissue concentrations
“Thus, the results show that oral GSH can
increase GSH concentrations in several
tissues following GSH depletion, such
as can occur in toxicological and
pathological conditions in which GSH
homeostasis is compromised. ”
•
Aw, T. et. al.Oral glutathione increases tissue glutathione in vivo. Chem
Biol Interact 1991;80(1):89-97
Oral glutathione increases
tissue concentrations
“Oral administration of GSH to these
GSH-deficient animals gave statistically
significant
increases
in
GSH
concentrations in kidney, heart, lung,
brain, small intestine and skin but not in
the liver ”
Aw, T. et. al.Oral glutathione increases tissue glutathione in vivo. Chem
Biol Interact 1991;80(1):89-97
Glutathione improves
occupational chemical
exposure
“When the endogenous GSH content was
reduced by pretreatment of the cells with Lbuthionine (S,R)-sulfoximine, the cytotoxicity
of the herbicides increased strongly in both
cell lines”
Dierickx PJ. Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides
alachlor, metolachlor, and propachlor in rat and human hepatoma-derived cultured
cells. Cell Biol Toxicol. 1999; 15(5): 325-32.
Glutathione improves
occupational chemical
exposure
“Different interactions with xenobioticmetabolising phase I and II enzymes
were observed, and GSH showed a
protective effect against the acetanilides
in both cell lines”
Dierickx PJ. Glutathione-dependent cytotoxicity of the chloroacetanilide
herbicides alachlor, metolachlor, and propachlor in rat and human
hepatoma-derived cultured cells. Cell Biol Toxicol 1999;15(5):325-32
Glutathione Plays a Major Role
in Heavy Metal Detoxification
Glutathione has been shown to be a
significant factor in heavy metal
mobilization and excretion, specifically
with mercury, cadmium and arsenic.
Patrick L. Mercury Toxicity and antioxidants: Part 1: Role in glutathione
and alpha lipoic acid in the treatment of mercury toxicity. Alt Med Rev
2002;7(6):456-471
Glutathione Plays a Major Role
in Heavy Metal Detoxification
Glutathione
depletion
and
glutathione
supplementation have specific effects on
mercury toxicity, both by altering antioxidant
status in the body and by directly affecting
excretion of mercury and heavy metals in the
bile
Patrick L. Mercury Toxicity and antioxidants: Part 1: Role in
glutathione and alpha lipoic acid in the treatment of mercury
toxicity. Alt Med Rev 2002;7(6):456-471