Transcript Toxic Metals in Humans

Glutathion- afgiftningens dirigent
Eva Lydeking-Olsen
2014
Hvad er glutathion?
• Glutathion er et tripeptid, bestående af de
tre aminosyrer
• Glutamin
• Cystein
• Glycin
• Glutathion (GSH) dannes i mange arter:
PLANTER
DYR
SVAMPE
nogle BAKTERIER og ARKEbakterier
- den aktive form beskytter mod skader på
cellekomponenter forårsaget af frie
radikaler
•
Pompella, A; Visvikis, A; Paolicchi, A; Tata, V; Casini, AF (2003). "The changing faces of glutathione, a cellular protagonist". Biochemical
Pharmacology 66 (8): 1499–503. doi:10.1016/S0006-2952(03)00504-5.
Glutathion har mange funktioner
• Glutathion er hovedanti-oxidanten, produceres af de fleste celletyper
•Deltager DIREKTE I neutraliseringen af frie radikaler og reaktive ilt-molekyler
•Recirkulerer exogene antioxidanter som C og E vitamin
•Scholz RW. Graham KS. Gumpricht E. Reddy CC. Mechanism of interaction of vitamin E and glutathione in the
protection against membrane lipid peroxidation. Ann NY Acad Sci 1989:570:514-7. Hughes RE. Reduction of dehydroascorbic
acid by animal tissues. Nature 1964:203:1068-9.
Glutathion har mange funktioner
•Regulerer NO-cyklus som er nødvendig for livets opretholdelse,
men kan være problematisk, hvis den mangler regulation
•Clementi, Emilio;
Smith, Guy Charles;
Howden, Martin;
Dietrich, Salvador;
Bugg, S; O'Connell, MJ;
Goldsbrough, PB;
Cobbett, CS
•(1999).
"Phytochelatin
synthase genes from
Arabidopsis and the
yeast
Schizosaccharomyces
pombe". The Plant cell
11 (6): 1153–64
Glutathion har mange funktioner
•Bruges i metaboliske og biokemiske reaktioner som
•DNA syntese – og reparation,
• protein-syntese,
•prostaglandinsyntese,
•aminosyretransport,
•enzym-aktivering
•ALLE vævs-og organsystemer i kroppen kan derfor blive påvirket af
glutathionstatus, specielt
•Immunsystemet
•Nervesystemet
•Mavetarmkanalsen
•Lungerne
•Vigtig i jern-metabolismen
Glutathione reduces disulfide bonds formed within cytoplasmic
proteins to cysteines by serving as an electron donor. In the
process, glutathione is converted to its oxidized form,
glutathione disulfide (GSSG), also called L-(–)-glutathione.
Once oxidized, glutathione can be reduced back by glutathione
reductase, using NADPH as an electron donor.[3] The ratio of
reduced glutathione to oxidized glutathione within cells is often
used as a measure of cellular toxicity.[4]
http://www.nature.com/cdd/journal/
v12/n12/fig_tab/4401754f1.html
Glutathion i Autoimmun Sygdom
•Modificerer vævs-TH1 og TH2
funktion, dvs den overordnede
balance i immunsystemet
•Aktiverer TH-3 regulatoriske Tceller
•Dæmper TH-17 aktivitet
- dette mindsker vævsdestruktion
pga autoimmunitet
•Øger vævs- og tarm-regeneration,
• Beskytter mitokondrierne
- hvilket øger helingsevnen
•N-acetyl-cysteine
•Alpha lipoic acid
•L-glutamine
•Selenium
•Cordyceps
•Centella asiatica
•Silybum marianum
•Broccoli extract
Aldring
Aldring
ift
glutathion
Aldring ift glutathion
Hvilke toxiner skal håndteres?
• Fødevare-afledte
toksiner
Miljøbelastninger:
• Tungmetaller
• Kemikalier, PCBs mm
• Medicinrester
• Affaldsstoffer fra
vores eget stofskifte:
• Oxidativ stress
• Inflammationstriggere
Fordele ved at varme maden op
Fordøjelighed& energitæthed
Mindske
ANTInutrienter
Fytin
Trypsinhæmmer
e
Hæmagglutinine
r/ Lektiner
Saponiner
Tanniner
Denaturering proteiner
Stivelse-forklistring
Biotilgængelighed carotenoider oma
Opvarmning
Hygiejne
*DESTRUKTION AF
Virus
Bakterier
Parasitter
Energimæssig
e faktorer
& balancer
Yin/Yang
Syre/base
Enzymer
Livskraft
Dannelse af toxiner ved opvarmning
Oxidation
af
kolesterol
Acrylamid
Heterocykliske
aminer (HCAs)
Polycykliske
aromatiske
hydrocarboner
(PAHs).
Advanced
Glycation
Endproducts
Dannelse af toxiner ved opvarmning
Acrylamid
.
Acrylamide…..
Effects of consumer food preparation on acrylamide
formation.
Jackson LS, Al-Taher F. Adv Exp Med Biol. 2005;561:447-65
Source U.S. Food and Drug Administration, National Center for Food Safety and Technology (NCFST), 6502 S. Archer Rd.,
Summit-Argo, IL 60501, USA. [email protected]
Abstract
Acrylamide is formed in high-carbohydrate foods during high temperature
as frying, baking, roasting and extrusion. Although acrylamide is known
to form during industrial processing of food, high levels of the chemical
have been found in home-cooked foods, mainly potato- and grain-based
products.
This chapter will focus on the effects of cooking conditions (e.g.
time/temperature) on acrylamide formation in consumer-prepared foods,
the use of surface color (browning) as an indicator of acrylamide levels
in some foods, and methods for reducing acrylamide levels in homeprepared foods.
As with commercially processed foods, acrylamide levels in homeprepared foods tend to increase with cooking time and temperature.
Acrylamide…………
In experiments conducted at the NCFST, acrylamide levels in cooked food
depended greatly on the cooking conditions and the degree of "doneness", as
measured by the level of surface browning.
• French fries fried at 150-190 ˚C for up to 10 min had acrylamide levels of 55 to
2130 microg/kg (wet weight), with the highest levels in the most processed
(highest frying times/temperatures) and the most highly browned fries.
• "dark" toasted bread slices had 43.7-610.7 microg/kg wet weight, compared to
"light" at 8.27-217.5 microg/kg or "medium" at 10.9-213.7 microg/kg
•Analysis of the surface color by colorimetry indicated that some components of
surface color ("a" and "L" values) correlated highly with acrylamide levels.
•Soaking raw potato slices in water before frying was effective at reducing
acrylamide levels in French fries.
•Additional studies are needed to develop practical methods for reducing
acrylamide formation in home-prepared foods without changing the acceptability
of these foods.
The effect of domestic preparation of some potato
products on acrylamide content.
Michalak J, Gujska E, Klepacka J. Plant Foods Hum Nutr (2011) 66:307–312
Source Food Science Department, University of Warmia and Mazury, ul. Heweliusza 6, Olsztyn, Poland. [email protected]
Abstract
The influence that food heating has on the concentration of acrylamide in home-cooked potato dishes prepared
by high-temperature, such as pan-frying, deep-frying, roasting and microwave heating was analyzed.
The experiment was performed with commercially available deep-frozen par-fried French fries and
deep-frozen par-fried potato products other than French fries (cubes, wedges, noisettes, pancakes).
Acrylamide was found in all deep-frozen par-fried French fries and other deep-frozen par-fried potato products
before domestic preparation. The mean level of acrylamide content in all frozen potato products before
preparation was found to be 322 μg/kg. Potato products were then prepared at 180 °C for 3 min and at 220 °C for 10 min.
After domestic preparation (roasting, pan-frying, deep-frying and microwave heating) it was found that the
level of acrylamide in all products increased. Acrylamide content in the analyzed samples significantly increased
as the temperature and time of processing increased.
The statistical analysis showed significant differences (P < 0.05) for acrylamide content as
a function of food preparation. The level of acrylamide increased with the increased heating temperature and heating time.
Additionally, the preparation method of roasting was significantly
lower in acrylamide content (P < 0.05)
than the preparation method of microwaving although both preparation
methods used the same conditions (time and temperature).
These results suggest that microwaving might be more favourable
to the formation of acrylamide
than conventional heating methods, such as roasting.
A comparative study of acrylamide formation induced
by microwave and conventional heating methods.
Yuan Y, Chen F, Zhao GH, Liu J, Zhang HX, Hu XS. J Food Sci. 2007 May;72(4):C212-6
Source College of Food Science & Nutritional Engineering, China Agricultural Univ., Beijing, 100083, China.
Abstract
In this study, the formation of acrylamide upon treatment with microwave and conventional heating,
boiling, or frying was investigated in both Asn/Fru and Asn/Glc model systems and in potato chips.
Acrylamide levels were analyzed by HPLC method, which was confirmed by HPLC-MS/MS.
Present results in model systems showed that pH value had a complex influence on the formation of
acrylamide in the 2 systems during both microwaving (600 W) and boiling (120 +/- 1 degrees C).
At pH < 8.0, acrylamide content increased with increasing the pH value, reaching the maximum at pH 8.0
whereas acrylamide content decreased with the increase of pH. Regardless of pH and heating methods,
acrylamide content generally increased with increasing treatment time. Surprisingly, all present results showed
that microwave heating not only induced acrylamide formation in the 2 model systems but also facilitated more
acrylamide to be formed as compared to the boiling method at identical pH and treatment time. At pH 4.0, 8.0, and 10.0,
the larger the microwave power, the more the acrylamide content.
Consistent with the above
observation, treatment of potato chips with microwave heating
for 2.5 to 3.5 min in the range 550 to 750 W similarly
resulted in acrylamide formation.
The highest acrylamide content was formed by 750 W
microwave treatment as 0.897 +/- 0.099 mg/kg, which was
significantly higher than that produced by traditional frying
(180 +/- 1 degrees C), 0.645 +/- 0.035 mg/kg (P < 0.05).
Statistical analysis for the effect of preparation methods
on the acrylamide content of potato products, (μg/kg)
Method
Before final
preparation
Pan-frying
Deep-frying
Roasting
Microwaving
French fries,
n = 11,
Other potato
products,
n = 12,
All products,
n = 23,
B416±61a
C252±72a
D322±154a
B561±53b
C400±46b
D469±109b
B597±67b
C418±53b
D495±114b
B727±71c
C557±51c
D630±100c
B790±64d
C676±59d
D725±107d
A Mean ± standard deviation,
a, b, c, d – Mean in columns followed by the same letter are not significantly different (P ≤ 0.05)
Acrylamide………..
• Less AA with MW in popcorn compared to conventional
heating , but high levels in sugar- varieties Wei Sheng Yan Jiu. 2007
Mar;36(2):220-2
• No formation of AA in cooking of vegetables in MW
•
Shokuhin Eiseigaku Zasshi. 2004 Feb;45(1):44-8.
• Higher formation of AA in selected vegetables if pre-cooked in
MW and then baked, compared to pre-cooking by boiling and
then baking Shokuhin Eiseigaku Zasshi. 2004 Feb;45(1):44-8.
Toxicology and Applied Pharmacology
Volume 118, Issue 2, February 1993, Pages 233–244
Synergistic Neurotoxic Effects of Styrene Oxide and Acrylamide:
Glutathione-Independent Necrosis of Cerebellar Granule Cells
Abstract
Conjugation with glutathione (GSH) is a mechanism of detoxification of acrylamide (ACR);
hence, prior depletion of GSH might be expected to
exacerbate ACR′s neurotoxicity.
GSH levels in female rats were reduced by ip administration of styrene oxide (SO; 250 mg/kg),
diethylmaleate (DEM; 0.5 ml/kg), or 2-vinylpyridine (VP; 100 mg/kg) 1.5 or 2 hr prior to
a single dose of ACR (100 mg/kg).
The time course of GSH depletion following treatment showed that all three regimens were
equally effective in reducing GSH in liver,cerebellum, cerebral cortex, and hippocampus
GSH levels in the liver were reduced to 4-22% , 2 and 4 hr after treatment
and to 38-57% of control levels in all brain regions between 4 and 8 hr.
ACR alone (100 mg/kg) reduced both brain and liver GSH to about 60% of normal.
The administration of a second dose of ACR (also 100 mg/kg) 12 hr later further depleted brain
and liver GSH to 33% of control.
Grillet kød
er farligt
Heterocykliske aminer (HCAs)
HCAs dannes ved meget høj temperatur eller
flammer
Forskellige HCAs dannes, som amino-imidazoquinolin, amino-imidazo-quinoxaliner, aminoimidazo-pyridiner, and aminocarboliner.
HCAs forårsager DNA skader og er formentlig en
faktor I udviklingen af forskelige kræftformer
Polycykliske aromatiske hydrocarboner
(PAHs).
PAHs dannes når fedt drypper ned på grillkullene og ryger…fx.benzo- pyren og
dibenzo[a,h]anthracen, som klistrer sig på
kødets yderside. Kræftfremkaldende.
.
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. Oct 2011; 29(4): 324–357
Polycyclic Aromatic Hydrocarbons and
digestive tract cancers - a perspective
Abstract
Cancers of the colon are most common in the Western
world. In majority of these cases, there is no familial
history and sporadic gene damage seems to play an
important role in the development of tumors in the
colon. Studies have shown that environmental factors,
especially diet, play an important role in susceptibility
to GI tract cancers. Consequently, environmental
chemicals that contaminate food or diet during its
preparation becomes important in the development of
GI cancers. Polycyclic aromatic hydrocarbons (PAHs)
are one such family of ubiquitous environmental
toxicants. These pollutants enter the human body
through consumption of contaminated food, drinking
water, inhalation of cigarette smoke, automobile
exhausts, and contaminated air from occupational
settings. Among these pathways, dietary intake of
PAHs constitutes a major source of exposure in
humans.
Country
Table 1
Estimated dietary intakes of PAH for various
countries
*Data pertain to benzo(a)pyrene intake only.
+Data was collected from intake of cooking oils.
#Data was collected from consumption of fish &
other seafood items only.
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev.
Oct 2011; 29(4): 324–357.
Polycyclic Aromatic
Hydrocarbons and
digestive tract cancers - a
perspective
Australia*
Austria
Brazil
China
Czech Republic
Denmark
Finland
France
Germany
Greece
India+
Italy*
Japan*
Netherlands
Newzealand*
Nigeria*#
Norway
South Korea#
Spain
Sweden
U.K.
U.S.A.
Estimated intake
(μg/person/day)
0.03
0.39
2.90
3.56
0.19
0.02
2.34
0.09
0.19
0.005
11.0
0.2
0.09
0.52
0.16
6.0
0.02
1.10
0.11
0.08
0.06
0.05
Fornuftigere brug af grill……..
1.Magert kød.
-drypper mindre fedt og dermed
mindre PAH-fyldt røg
2.Mariner kød før grill´ning
HCA kan reduceres med op til 90 % ,
måske barrierefunktion
3.Lavere temperatur
4.Undgå flammer
Flammer forårsager både HCAs og
PAHs.
5.Oversteg IKKE kødet.
Fjerkræ , fisk, skaldyr og hakket kød
skal gennemsteges, men ikke mere
end det, brug termometer.
Afgiftning af HCA og PAHs
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. Oct 2011;
29(4): 324–357
Leverafgiftning, Fase 2
Methylering
Sulfatering
Enzym
Cofaktor
GlutathionTransferaser
S-adenosylmethionin
SAM
Cystein,
glycin
glutamin
Cobalamin,
Folat,
Methionin
Betain
(rødbede)
Sibylum
Marianum
(marietidsel)
Flavonoider
Arctium lappa
(glat burre)
Salvia
Officinalis(salvie)
Andet
N- og O-methyltransferaser
Variationer
Genetiske
variationer fra
gennemsnitlig
afgiftingsevne er
alminderlige
1)DHEA - dehydroepiandrosteron
2)CCK - cholecystokinin
Acetylering
Konjugering
Sulfotransferase
Aminosyre-transferaser
N-acetyltransferaser
Glucuronidering
Glucuronyltransferaser
PAPS (phosphoadenosin,
phosphosulfat)
Acetyl CoA, Taurin,
Glycin
UDPG, (Urinidin
diphosphoglucuron-syre)
B1 – vitamin (thiamin)
B2-vitamin (riboflavin)
B3-vitamin (niacin)
B5 – vitamin
(pantotensyre),
Lipoinsyre (svovlholdigt
B5 vitaminlignende stof)
Mucopolysaccha
rider: Aloe Vera,
Reishi-svamp,
Shiitake-svamp,
Kombucha-the
Grøn the
Svovlholdige
fødemidler: bønner,
æg, løg, hvidløg,
MSM-tilskud,
Alle proteiner
Methionin
Cystein
Genetisk forskel på om
man er hurtig eller
langsom i dette
afgiftningstrin, ca. 50 % i
hver gruppe.
Methylerin
g
Enzym
N- og Omethyltransferaser
Paraquat
Isoquinoliner
Kviksølv
Bly
Arsen
Tallium
Tin
Pyridin
Sulfatering
GlutathionTransferaser
Styren
Acrolein
Benzpyren
Methylparathion
(sprøjtemiddel)
Chlorobenzen
Anthrazen
Tetraclorvinfos
Giftige metaller
Oliedestillater
Naphtalen
PCB
Sulfotransferase
Anilin
Fenolforbindelser
Terpener
Aminer
Hydroxylaminer
Phenoler
PCB
Acetylering
Aminosyre-transferaser
N-acetyltransferaser
Benzosyre
Fenyleddik
esyre
Naftyleddi
kesyre
Alifatiske
/aromatiske
aminer
Organiske
syrer
Propionsyr
e
Kaprylsyre
2-aminoflourin
Anilin
Konjugering
Glucuronidering
Glucuronyltransferaser
Carbamater
Fenoler
Thiofenoler
Anilin
N-OH-2naftylamin
PAH=
polychlorerede
aromatiske
hydrocarboner,
inkl.
Stegemutagener,
epoxider
HCA
PCB
Methylering
Enzym
N- og Omethyltransferaser
Dopamin
Adrenalin
Histamin
Noradrenalin
L-dopa
Apomorfin
Hydroxyøstradi
ol
Sulfatering
GlutathionTransferaser
Sulfotransferase
Bakterietoksiner
Aflatoksin
Lipidperoxider
Etanol (alkohol)
Quercetin
N-acetylcystein
Prostaglandiner
Bilirubin
Leukotrien A
DHEA1)
Quercitin
Galdesyrer
Tyramin
Tyroxin
Østrogener
Testosteron
Cortisol
Catecholamine
Melatonin
Coumarin
Vitamin D
Etanol (alkohol)
CCK2)
Cerebrocider
1)DHEA - dehydroepiandrosteron
2)CCK - cholecystokinin
PABA - para-aminobenzoesyre
Acetylering
Konjugering
Aminosyre-transferaser
N-acetyltransferaser
Galdesyrer
PABA3)
Organiske
syrer
Serotonin
PABA
Histamin
Tryptamin
Koffein
Cholin
Tyramin
Coenzym A
Galdesyrer
Stearinsyre
Palmitinsyr
e
Myristinsy
re
Laurinsyre
Smørsyre
Glucuronidering
Glucuronyltransferaser
Bilirubin
Østrogener
Melatonin
Galdesyrer
Vitamin E
Vitamin A
Vitamin K
Vitamin D
Steroidhormoner
Advanced
Glycation
Endproducts
AGEs
Advanced
Glycation
Endproducts
AGEs
AGEs- advanced glycation endproducts
– Maillard reaction / roasting process
Oxidativt stress
Nedsat organ-reservekapacitet
Nedsat organ-funktion
Øget træk på reparationssystemer
(celledeling)
Telomerer……når de er slut,
deler cellen sig ikke mere
Aldring
Nutrients. Dec 2010; 2(12): 1247–1265.
Published online Dec 13, 2010. doi: 10.3390/nu2121247
PMCID: PMC3257625
Dietary Advanced Glycation End Products and Aging
Claudia Luevano-Contreras* and Karen Chapman-Novakofski
Organsvigt:
Nyrer, lever, hjerne
AGEs in food………..
• Worst is high protein-high
fat foods w. endogenous
cellular sugar, producing
”glyco-toxins”:
• Meat, nuts, fats
• Worst is heating w. higher
temperature/ longer time
or ”maturing ” cheese
(parmesan)
J.Am.Diet.Ass.2010;110:911- 16
• Better is acidic
environment (marinade w.
lemon or vinegar)
• Better is shorter time, ie
MW
• Better is grains, vegetables,
pure sugar-foods and milk
products
AGEs in food…..database available
Food item
J.Am.Diet.Ass.2010;110:911-16
AGE, kU/100 g
Butter
Beef, raw
26.480
800
Beef, grilled 4 min
7.416
Beef, Microwaved , 6 min
2.687
Beef, pan fried , olive oil
10.058
BACON, 5 min no oil
91.577
BACON, 3 min MW
9.023
Chicken breast, skinless , raw
769
Chicken breast, skinless , pan fried 13 min, high
tp
4.938
Chicken breast, skinless , poached 15 min
1.076
Chicken breast, skinless , microwaved 5 min
1.524
…similar for many other protein rich foods……..
AGEs in food…..database available
J.Am.Diet.Ass.2010;110:911-16
Food item
Lamb, raw/ boiled 30 min
Parmesan vs. cottage cheese 1%
Egg, no oil, all types
Potato boiled vs. French fries
Cashew raw
Pine seeds, raw
Pistacie, raw
Sunflower raw vs. roasted
Peanuts Roasted vs. Roasted in shell
SOY beans roasted and salted
AGE, kU/100 g
826 /1.218
16.900/1.453
43-90
27 / 1522
6.730
11.210
380
2510/4693
8.333/3.440
1.670
AGEs optimalt niveau ?
• 6-8000 units = sund kost
• 10-12.000 units = problematisk
• 15-20.000 units = toxisk
Høj AGE
MORGENMAD
Frisk frugt
Spejlæg
Ristet bagel
Flødeost
Kaffe
Fløde
FROKOST
Bønnesuppe
Grillet kylling
Blandet grøn salat
Italian dressing
Kiks/knækbrød
Ice te
MELLEMMÅLTID
Æble
Amerikansk ost
AFTENSMAD
Grillet steak
Pommes frites
Dampede grøntsager
Smør
Frisk frugt
Lav AGE
Portion
1 kop
1
57 g
1 spsk
1 kop
1 spsk
AGE
30
1240
100
1500
5
325
1 kop
85 g
3 kopper
2 spsk
28 g
227 g
100
5200
50
220
275
5
1
28 g
15
2600
85 g
85 g
1 kop
1 tsk
1/2 kop
6600
690
20
630
15
TOTAL AGEs
AGEs fra
www.ncbi.nlm.nih.gov/pmc/articles/PMC3704564
19620
MORGENMAD
Frisk frugt
Scrambled æg
Frisk bagel
Margarine
Kaffe
Sødmælk
FROKOST
Bønnesuppe
Simret kylling
Blandet grøn salat
Italian dressing
Fuldkornsbolle
Ice te
MELLEMMÅLTID
Æble
Yoghurt
AFTENSMAD
Stegesos oksekød
Bagt kartoffel
Dampede grøntsager
Olivenolie
Frisk frugt
Portion
1 kop
1
57 g
1 tsk
1 kop
1/4 kop
AGE
30
75
60
180
5
3
1 kop
85 g
3 kopper
2 spsk
28 g
227 g
100
1000
50
220
25
5
1
170 g
15
10
85 g
85 g
1 kop
1 tsk
1/2 kop
2200
70
20
150
15
4233
Kyllingesalat jvf. Paleo-kost
AGE kU
23
1104
1210
27
1642
1657
502
_____________
6165 IALT
Afgiftning af AGEs
er betinget af:
*Glyoxalase I og II
Glutathion virker som coenzym
*Urinudskillelse
= god nyrefunktion, minimer
oxidativt stress= Glutathion
*Carbonyl reductase
Nature. 2005 Dec 1;438(7068):662-6. Epub 2005 Oct
23.
Glyoxalase 1 and glutathione reductase 1 regulate
anxiety in mice.
Hovatta I1, Tennant RS, Helton R, Marr RA, Singer O,
Redwine JM, Ellison JA, Schadt EE, Verma IM,
Lockhart DJ, Barlow C.
J Biol Chem. 2008 Dec 19;283(51):35756-62.
Human carbonyl reductase 1 is an
S-nitrosoglutathione reductase.
Bateman RL1, Rauh D, Tavshanjian B, Shokat KM.
Abstract
Human carbonyl reductase 1 (hCBR1) is an NADPHdependent short chain dehydrogenase/reductase with
broad substrate specificity and is thought to be responsible
for the in vivo reduction of quinones, prostaglandins, and
other carbonyl-containing compounds including
xenobiotics. In addition, hCBR1 possesses a glutathione
binding site that allows for increased affinity toward
GSH-conjugated molecules. It has been suggested that the
GSH-binding site is near the active site; however, no
structures with GSH or GSH conjugates have been
reported. We have solved the x-ray crystal structures of
hCBR1 and a substrate mimic in complex with GSH and
the catalytically inert GSH conjugate
hydroxymethylglutathione (HMGSH). The structures
reveal the GSH-binding site and provide insight into the
affinity determinants for GSH-conjugated substrates.
Oxidation af kolesterol
Intact LDLcholesterol
Oxidized cholesterol,
broken apart – particles
infiltrates arterial wall
LDL cholesterol appears intact in the lower-left corner while
oxidized
cholesterol that has broken apart is shown in the
background as it infiltrates the damaged arterial wall along with
red www.renderosity.com/.../folder_9/file_435308.jpg
blood cells.
Primary
cholesterol
oxygenation
reactions
mediated by
* Cytochrome
P-450 species
*Occurring nonenzymatically in
the presence of
reactive oxygen
species (ROS)
Oxygenation of
cholesterol into
25-OH cholesterol
is catalyzed by
cholesterol 25hydroxylase, a
non-heme iron
protein
Björkhem 2002
Oxycholesterol boosts total
cholesterol levels
Promotes atherosclerosis more than nonoxidized cholesterol.
Fried and processed food, particularly fastfood, contains high amounts of oxycholesterol.
Avoiding these foods and eating a diet rich in
antioxidants: Fresh fruits, berries and
vegetables, may help reduce its levels in the
body.
Added to processed foods, those substances
improve texture, taste and stability
Source: 238th National Meeting of the American
Chemical Society 2009. Zhen-Yu Chen, PhD
Chinese University of Hong Kong
(Photo Credit: Wikimedia
Commons)
Alzheimer's and oxidized cholesterol:
Neighbors come together
An oxidized form of cholesterol alters membrane
organization and might disrupt cellular function in
Alzheimer's disease.
Alzheimer's disease is characterized by accumulation of the
neurotoxic peptide β-amyloid. This peptide can oxidize
cholesterol to form the oxysterol 7β-hydroxycholesterol 1 (7βOH). Although cholesterol in cell membranes brings
7β-hydroxycholesterol is produced by
neighboring phospholipid molecules closer together, by
oxidation of cholesterol
inducing a partial straightening of their acyl chains, the
effect of 7β-OH on membrane organization is unknown.
Now Steven Regen and colleagues report in the Journal of
the American Chemical Society that the condensing effect of
7β-OH is enhanced compared to that of cholesterol. This
Mitomo, H., Chen, W.H. and
Regen, S.L.
produces a membrane reorganization that might help to
Oxysterol-induced rearrangement
explain the enigmatic etiology of Alzheimer's disease.
of the liquid-ordered phase: a
possible link to Alzheimer's
disease?.
J. Am. Chem. Soc. (6 August
2009). doi:10.1021/ja904308y
Oxidized cholesterol test feeding
Background: Information on the absorption of cholesterol oxidation
products (COP) from ordinary foodstuff in humans is scarce.
Methods: Five healthy young men were offered a 150 g salami + 150 g
Parmesan+ 135 g bread, a meal naturally rich in COP. Plasma and
lipoprotein COP concentrations were measured over 9 h.
Results: The mean plasma free (nonesterified) COP concentration showed its
maximal increase 3 and 5 h after meal consumption. In contrast, the raise in
plasma total COP concentration began 6 h after the meal with a maximum
at 8 h and was statistically significant for 7·- and 7ß-hydroxycholesterol
and 7-ketocholesterol.
Conclusion: COP from ordinary foodstuff were absorbed
in the human intestinal tract but differences in the bioavailability of the
single COP compounds were found.
Dr. Jakob Linseisen/ Günther Wolfram Institute of Nutrition Science of the Technical University of Munich, Germany.
Ann Nutr Metab 1998;42:221–230
Peak 3 hrs.
• Alpha- epoxide
• 7- keto :
triple from 75,4 nmol/l at
baseline to 235 nmol/l
• Cholestanetriol
Peak at 5 hrs.
• 7- α – OH- cholesterol
• 7-β – OH- cholesterol
Doubles from 40 nmol/l
to 87 nmol/l
• Cholesterol- β- epoxide
25-OH- Cholesterol
The role of endoplasmic reticulum stress in the progression of
atherosclerosis.
Tabas I. Circ Res. 2010 Oct 1;107(7):839-50.
Prolonged activation of the endoplasmic reticulum (ER) stress
pathway,known as the unfolded protein response (UPR) can
lead to cell pathology and subsequent tissue dysfunction.
Ample evidence that the UPR is chronically activated in
atherosclerotic lesional cells, particularly advanced lesional
macrophages and endothelial cells.
The stressors in advanced lesions that can lead to prolonged
activation of the UPR include oxidative stress, oxysterols,
and high levels of intracellular cholesterol and saturated fatty
acids.
Oxycholesterol- biological effects
Oxycholesterol, may pose the greatest heart
disease risk.
Study on hamsters (Chen, Hong-Kong 2009):
•Diet high in oxycholesterol Vs.
Diet with non-oxidized
cholesterol
Outcome :
•Blood cholesterol + 22 % in oxy-cholesterol group
•Greater deposition of cholesterol in the lining of blood-vessels
(atherosclerotic plaques)
Plaques increase the risk for heart attack and stroke.
Oxycholesterol had undesirable effects on artery function:
Reduces the elasticity of arteries, impairing their ability to expand and
carry more blood.
Second heating study
Time-of-year-result, study 1 + 2
T-test May vs.
January
p-value
Raw
0,321
MW
0,001
Oven
Boiling
0,001
0,001
Pooling of data, first study
1400.0
1200.0
1000.0
All 3 oven methods were similar: Convection,
hot-air and common electric oven, n=18
Two boiling methods: Water boiling on
electric stove and pressure boiling on electric
stowe, n=12
Three frying methods: Teflon pan, easy slip
800.0
Alpha-Epoxy
7-beta-OH
7-Keto
600.0
Beta-Epoxy
Total oxy
400.0
200.0
0.0
Wok gas,n=6 Induction, n=6
Raw,n=3
All oven,
n=18
Boiling, n=12 Frying,n=18
MW, n=6
Steaming,n=6
Second heating study
Overall result, n=12 raw and n=9 in each group
Overall ranking from
high to low, at
significant p-values:
1. boiling
2. MW
3-6. similar: wok,
steaming, oven,
induction
7. teflon
8. control
Intermediate/ Selected methods heating study
Fig.12.
7-beta-OH-cholesterol
Stepwise regression: group, at p=0,026 and weight
change at P=0,028
Univariate analysis w. Bonferroni at 0,01
*Control significantly different from:
- Boiling, MW and oven
*Wok gas significantly different from:None
*Boiling significantly different from:
- Control, teflon, steaming, induction and oven
*Teflon significantly different from:
- Boiling, MW
*MW significantly different from:
- Control, teflon, steaming, induction, oven
*Steaming significantly different from:
- MW, boiling
* Induction significantly different from:
- Boiling, MW
*Oven significantly different from:
- Control, boiling, MW
Added spices…….and a good quality oil
 Organic greek extra- virgin olive oil
w. lemon – 1 tbs. In preparation
 Organic rosemary (Rosmarinus
Officinalis), from
www.Sonnentor.com ≈ 3 tsp. added
before heating
 Organic/bio turmeric (Curcuma)
from www.lebensraum.de ≈ 3 tsp.
added before heating
 Let sit for 15 min before preparation
 Level of spices high, compared to
European tradition, but with fine
taste.
7-betaHydroxycholesterol
after heating with
spices turmeric,
rosemary and olive oil,
n=2
300.0
250.0
200.0
150.0
100.0
50.0
0.0
7-beta-Hydroxycholesterol
1. Slight increase in MW +
spices,
2. Large increase in
induction + spices, almost 3fold from 87 ng/g to 263 ng/g
Beta-Epoxy-cholesterol
after heating with
antioxidant spices turmeric,
rosemary and olive oil, n=2
500.0
450.0
400.0
350.0
300.0
250.0
200.0
150.0
100.0
50.0
0.0
beta-Epoxycholesterol
1. 58% decreased oxidation in
MW + spices,
2. 38 % increase in induction +
spices
3. 17% % decreased oxidation in
Conclusion
• The study has revealed a significant trend for formation of COPs in
different heating methods of organic chicken breast.
• Study 1:
Wok, teflon pan and Induction = gentle heating
Electric heating = intermediate, regardles of method
Steaming, boiling and microwave = aggressive.
• Study 2:
Teflon (green pan) = gentle
Wok, streaming, oven, induction= intermediate
Boiling, microwave = aggressive
Indian Journal of Experimental Biology
Vol. 43, June 2005, pp. 503-508
Effect of cholesterol and 7- hydroxycholesterol on
glutathione status
and nitric oxide production in murine peritoneal
macrophages M P Bansal & Sonia Shalini
Present study was conducted to observe the effect of cholesterol and oxidized cholesterol
(7-hydroxycholesterol,7-OH) on the nitric oxide (NO) production and the redox ratio
by lipopolysaccharide-stimulated macrophages. Dose-dependent decrease in NO levels
was seen with both cholesterol and 7β-OH at different incubation intervals (6,12,18,24 hr)
and concentrations (2.5,5,7.5g/ml). On comparison, a significant decrease in the NO was
observed at 24 hr interval in 7-OH exposed cells with all respective concentrations of
cholesterol. Incubation with 7-OH also resulted in significant increase in levels of
oxidized glutathione (GSSG) and decrease in reduced glutathione (GSH), while
cholesterol showed no effect on GSSG levels. Moreover, GSH levels were lowered only at
highest concentration (7.5g/ml), and at longer incubation intervals (18,24 hr) with
cholesterol exposure. This altered the redox status in both cholesterol/7-OH treated
macrophages. Increased redox ratio and decreased NO levels indicated increased
oxidative stress and decreased vasodilation by 7-OH compared to cholesterol.
Keywords: Cholesterol, Glutathione status, 7- Hydroxycholesterol, Murine peritoneal
macrophages, Nitric oxide
Konklusion
• INGEN enkle
resultater eller
handlinger på
området
• VARIATION
Kulhydrater
/stivelse:
hellere kogt
/langtidsbagt
ved lav
temperatur
/ låg på
Grøntsager:
Mange RÅ,
Nogen kan
lide
opvarmning
Proteiner
& fedt:
Så LAV
temperatur og
så KORT tid
som muligt
Glutathion i udviklingsforstyrrelser
ADHD og autisme
“Glutathione is the major
antioxidant present in
cells and is responsible for
detoxification and
elimination of
environmental toxins.
It’s active form is
reduced 80% in kids with
autism”.
HVEM ønsker sig mere glutathion
???
= BESKYTTELSE MOD
OXIDATIVT STRESS,
UNØDIG ALDRING,
BESKYTTELSE AF BLODKAR,
NYRER, HJERNE, HJERTE, LEVER OG
ALLE CELLER ?
BESKYTTELSE IFT ANGST OG URO?
Master detoxifier´s
Sublinthion
• For første gang findes
nu et effektivt
glutathionprodukt:
• Biologisk aktivt
• Optages gennem
mundslimhinden
Tak for i dag
SPØRGSMÅL??
Possible to reach high enough levels
of COP with 75°C heated chicken ??
Amount of COP per portion of 150 g edible portion ≈ 50 g dry weight
7-beta -OH, a-epoxy,
nmol
nmol
7- keto,
nmol
b-epoxy,
nmol
Total oxy
cholesterol
nmol
15,74
123,61
23,61
107,75
270,72
Teflon pan 27,50
113,50
57,00
271,50
469,94
MW
90,50
158,00
180,00
532,00
960,00
Boiling
117,01
200,20
205,76
625,31
1148,28
Raw
Metals and Metal-toxicity:
• Essential minerals are
• Act as antagonists to
used to chelate and
essential nutrients,
secrete toxic metals.
especially minerals
E.g.: high limit of
and trace minerals.
copper or cadmium
Humans differentiate
pushes out zinc,
between e.g. zinc and
producing symptoms
cadmium, but will take
of defiencency and
up cadmium in lack of
toxicity
zinc.
simultaneously.
Metals and Metal-toxicity:
• The balance between
the minerals can be
disrupted. E.g. low
limit of zinc will
interfere with limits of
iron and manganese producing problems in
cellsignaltransmission
and energiproduction.
• Long-term low-dose
exposure can affect
immune-, hormoneand nervesystem to
shut down the ability
absorb nutrients,
thereby producing a
condition of being
resistant to therapy.
Metal-toxicity:
• Direct toxic effect,
with organ-damage,
especially in organs
where metals upconcentrate. Anything
below ”High limit”
does not mean that
sensitive humans
could not be affected
by akkumulation.
• Free radical effect,
damaging cells and
cellmembranes,
disturbing energymetabolism and ability
to detoxify. Higher
demand for antioxidants.
Detoxification Through Food:
• Be sure to get enough nutrients to work as
antagonists to metals. Food intolerance is often an
issue. Supplements are often required.
• Be sure to get enough fiber to bind whatever is
secreted in the intestines.
• Be sure to get enough fluid to secrete sufficiently
through the kidneys, possibly with golden rod
herbal te.
Detoxification Through Food:
• Adequate intake of sulphurcontaining
nutrients, which has a remarkable capacity
to chelate toxic metals:
• Eggyolk, onions, garlic, beans and lentils.
All you can eat and digest. Tofu is easier to
digest. Beans and lentils contain much fiber,
proteins, vitamins, minerals and
traceminerals.
Detoxification Through Food:
• Seaweed, alganit chelates mercury and
radioactivity. Use it in flour, salads and rice.
• Wholemeal products and vegetables
(spinach) to provide B-vitamins (folic acid)
• Optimal fats – koldpressed plantoils and
olive oil.
• Sufficient protein intake for the immune
system and blodsugar-balance.
Detoxification Through Food:
AVOID:
•
•
•
•
•
Sugar
Milk
Alcohol
Cheese
Coffeine
Tobacco
Soda waters
Simple carbohydrates
Other items that create biochemical and
emtionel chaos.
Supplements:
• Vitamin C – allround detoxifier. From 1.5
to 8-10 grams is necessary. Cadmium and
mercury require high amount, lead lower.
• Mixed vitamin and mineralsupplement,
preferably with organic selenium and folic
acid (over 200 microgram).
• Management of gut-dysbiosis
Other Issues:
• Sauna 2-3 times a week, aids in detoxification through the skin. Lots of water.
• Baths with bicarbonet and magnesiumsulfate, 1 handfull of each
• Dryrubbing stimulates skinfunction.
Disulfide relays and phosphorylative cascades: partners in
redox-mediated signaling pathways
G Filomeni, G Rotilio and M R Ciriolo
Table 1. Different modalities of oxidative stress
[ROS] oxidative stress
Effect
Antioxidants implicated
Response
in cell response
Target
GENERAL
HEAVY (pathological)
Irreversible oxidative
damage
Cellular macromolecules Enzymatic defense (SOD,
Nonprogrammed events:
(Proteins, DNA, lipids) GPx, CAT)
GSH (cosubstrate and
scavenger)
1. Rescue/survival
2. NECROSIS
SPECIFIC
MILD (physiological)
Reversible oxidations
Transcription (NF-kB,
AP-1, p53)
Regulation of gene
transcription
Regulatory proteins (TRX,GSH, TRX (mediators of 1. Proliferation
GST)
cell signaling)
2. APOPTOSIS
Programmed events:
http://www.nature.com/cdd/journal/
v12/n12/fig_tab/4401754f1.html
Redox regulation of MAP kinases.
The scheme represents the intimate
relationship between phospho- and
redox-mediated signals. The
detachment of the redox-sensitive
inhibitory subunits, Trx and GST,
from ASK1 and JNK, respectively,
allows transforming an oxidative
stimulus in a phosphorylative
cascade
Previous figure |
Acrylamide content of potato products before final preparation
French fries
Crinkle, n=5 each
Thick-cut, n=3 each
Shoestring, n=3 each
(μg/kg)
Preparation methods
mean±SD
Before final preparation
410±41
Pan-frying
Deep-frying
Roasting
Microwaving
535±49
539±45
660±51
744±72
Before final preparation
358±81
Pan-frying
Deep-frying
Roasting
Microwaving
527±39
568±41
704±68
763±55
Before final preparation
480±11
Pan-frying
Deep-frying
Roasting
Microwaving
622±10
685±15
817±17
863±25
A Mean ± standard deviation, n = The
number of the same type of products
and after different domestic preparation methods ,
Acrylamide content of potato products before final preparation
and after different domestic preparation methods (μg/kg)
Other potato products Preparation methods
Cubes, n= 3 each
Wedges,n=3 each
Noisettes, n=3 each
Pancakes; n=3 each
Acrylamide (μg/kg)
Pan-frying
341±17
Deep-frying
Roasting
Microwaving
392±18
527±28
679±70
Before final preparation
197±18
Pan-frying
Deep-frying
Roasting
Microwaving
436±18
451±19
588±22
635±30
Before final preparation
337±16
Pan-frying
Deep-frying
Roasting
Microwaving
387±19
405±7
547±9
696±12
Before final preparation
286±2
Pan-frying
Deep-frying
Roasting
Microwaving
437±11
422±13
564±10
694±11
Frittata (æggekage)
AGE kU
1657
36
808
2936
501
___________
5938
Kyllingesalat
AGE kU
23
1104
1210
27
1642
1657
502
_____________
6165
Æg Benedict (hakkebøf med æg og grønt)
20%
AGE kU
9856
36
502
57
40
23
1104
2000-3000
502
______________
14620
Conclusion
• Findings are highly relvant for public health on
the real large scale…………it is findings who, if
applicated, studied and expanded further – can
contribute to save both lives and quality of lives.
• Alone i EU 25 (ie not worldwide) there is
741.000 coronary heart disease deaths, per year.
• Oxidized cholesterol is thought to be a major
contributing preventable cause.
Intermediate/ Selected methods heating study
Fig. 13. Total Oxy-cholesterol/Total
COPs
Stepwise regression: Group, at p=
0,024 and weight change p=0,045
Univariate analysis w. Bonferroni at
0,01:
*Control significantly different from:
Boiling, teflon, MW, steaming, oven
*Wok gas significantly different from:
none
*Boiling significantly different from:
- Control, teflon, induction
*Teflon significantly different from:
- Boiling, MW
* MW significantly different from:
- Control, teflon, steaming, induction
* Steaming significantly different from:
- Control, MW
*Induction:- Boiling, MW
*Oven significantly different from:
- Control