HLTH 340

Lecture A3

Toxicokinetic processes:

absorption (part-2) carrier-mediated transport

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W2013 HLTH 340 Lecture A3 1

• • • • Carrier-mediated absorption using membrane transport channels membrane transport channels – large glycoprotein molecules embedded in the phospholipid membrane – act as channels (pores) that allow specific hydrophilic solutes (e.g. metal ions) to cross membrane barriers – enables transcellular absorption of many hydrophilic ions and polar molecules 2 types of membrane transporter channels – –

active transport channels facilitated diffusion channels active transport

– increases rate of absorption – can concentrate (or remove) substance in tissues against a concentration gradient of a given solute (non-equilibrium; pumps solutes ‘uphill’) – requires energy source (e.g. ATP or other source of chemical energy)

facilitated diffusion (passive transport)

– increases rate of absorption – does not concentrate or eliminate substance in tissues (equilibrium only; no pumping) – no energy source required W2013 HLTH 340 Lecture A3 2

Types of transcellular membrane transport W2013 HLTH 340 Lecture A3 3

• • • Absorption of inorganic ions through membrane ion transport channels

each type of channel has a selective preference for transporting certain ions

– – specific solutes are preferred, but not absolutely specific factors determining ion transporter specificity include • ionic radius(size) • positive or negative charge • valency of the ionic charge • class of metal ion (alkaline metals, transition metals, heavy metals)

size and ionic charge determines selective transport thru ion channels

–

cation

transport channels (K + , Na + , Ca ++ , etc.) transport positively charged ions (e.g. metals) monovalent (+1), divalent (+2), trivalent (+3), etc.

–

anion

transport channels (Cl , I , ClO 3 etc.) transport negatively charged ions monovalent (-1), divalent (-2), trivalent (-3), etc.

factors affecting rate of transport

– – – –

affinity

(high-affinity ==> rapid transport) <-- determined mainly by ionic charge and the effective ionic radius

saturation

(rate-limiting factor for absorption speed)

competition

(2 substances compete for the same transporter channel)

regulation

(up-regulation or down-regulation by other physiological factors) W2013 HLTH 340 Lecture A3 4

Metal speciation • • • •

metals can exist in different physico-chemical states (species)

–

elemental (metallic)

–

oxidized (metal oxides and salts)

–

inorganic or organic compounds

metal speciation

– inorganic metals can have several different

oxidation states

– elemental (metallic) species, Me o neutral, no electric charge solid metal (e.g. Pb o ) or metal vapor (e.g. Hg o ) – oxidation states:

loss of electron (LEO) is chemical oxidation Me + loss of 1 electron is valence state (I) Me ++ Me +++ loss of 2 electrons is valence state (II) loss of 3 electrons is valence state (II)

different species of the same metal can vary widely in toxicity

–

example: chromium:

Cr-III (chromium three) -- oxidation--> Cr-VI (chromium six)

low toxicity high toxicity

organometallic compounds

– metal atom covalent linked to organic (carbon chain) group(s) – – – frequently very toxic lipophilic organometal compounds are especially hazardous

example: mercury

mercuric ion (Hg 2+ ) --> methyl mercury (organic)

low toxicity high toxicity

W2013 HLTH 340 Lecture A3 5

essential metals

Metal ions ‘ heavy metal ’ ions compete for membrane transport via

ionic mimicry precious metals (toxic, but rare) trivalent metals (too ionic or insoluble to be absorbed) toxic metals heavy metals (ionic mimicry) transition metals (absorbed via transport channels) alkali metals (absorbed via transport channels)

W2013 HLTH 340 Lecture A3 6

• • • • Intestinal calcium transport channels:

calcium (Ca ++ )

uptake competes with

lead (Pb ++ )

intestinal epithelium contains selective ion transport channels for different divalent cations (Ca ++ , Fe ++ , Zn ++ )

– each serves as a transcellular transport channel of divalent cations from the intestinal lumen into the bloodstream

example: calcium (Ca ++ )

– – – calcium is an essential metal nutrient paracellular uptake by passive diffusion is sufficient at high dietary calcium levels(strong conc gradient) transcellular carrier-mediated transport is required for low dietary concentrations of calcium Ca ++ uptake requires transcellular transport via a selective

divalent cation

calcium channel – – requires ATP energy to run the

active transport system (pump) selective

calcium absorption occurs from many foods (milk, dairy products, vegetables, fruits, fish)

TRPV6 (ECaC2) calcium channel

– Ca ++ is absorbed from the intestine to blood using indirect active transport via the

TRPV6

calcium channel – –

epithelial calcium channel type 2

(

ECaC2

; now termed

TRPV6

) carrier-mediated uptake by

TRPV6

is up-regulated by active vitamin D • sunlight / UV synthesis / melanization • vitamin D supplements in milk and other diary products also sustained by estrogen hormones (up-regulation)**

**ocurs only in females

1



, 25-(OH) 2 D3

lead (Pb ++ )

– – – lead exists as a divalent cation

(Pb ++)

-- the ion structure of lead mimics calcium ion

(ionic mimicry)

Pb ++ is absorbed from the intestine into the blood using same Ca ++ transport channel

(TRPV6

)

saturation-competition

occurs with calcium versus lead for saturable

TRPV6

channels in intestine W2013 HLTH 340 Lecture A3 7

Carrier-mediated transport is a saturable process that has a limited capacity to move solutes paracellular intestinal calcium absorption at high Ca ++ conc (passive diffusion) TRPV6 transport channel becomes saturated at high Ca ++ conc TRPV6 intestinal calcium absorption at low Ca ++ conc (carrier-mediated) W2013 HLTH 340 Lecture A3 8

Calcium ion transport channel embedded in epithelial cell membrane (TRPV6) Pb 2+ W2013 Ca 2+ HLTH 340 Lecture A3 9

Organized water ionic groups and polar groups

effective ionic radius

- ionic molecules and metal ions form electrostatic bonds with the surrounding water molecules, so that the ions actually have a much larger sphere of hydration than the notional size of the unhydrated metal ion -- the radius of the sphere of hydration determines the degree of penetration of the metal ion through a specific carrier-mediated transport channel

hydrogen bonding

- in hydrophilic polar molecules, the hydrogen in one or more functional groups (e.g. -OH) has a slight positive charge and is therefore attracted by the partly negatively charged oxygen of a nearby water molecule, with the result that a hydrogen bond is formed. The dissolved (solute) molecules and the water molecules thus become linked to one another. When non-ionic polar molecules form hydrogen bonds with the surrounding water molecules, the polar molecules are ‘ glued ’ to the water solvent layer -- this organized water layer must be stripped away before the solute molecule can penetrate through a narrow carrier mediated transport channel W2013 HLTH 340 Lecture A3 10

Ion transport channels - the

effective ionic radius

of hydration sphere for divalent cations W2013

effective ionic radius

- for ionic radius of metal divalent cations, the smaller ions have higher ionic potentials and form stronger bonds with water molecules, so that smaller ions actually have a larger sphere of hydration when entering into a specific ion transport channel HLTH 340 Lecture A3 11

Structure of the TRPV6 (ECaC2) tetrameric calcium channel using molecular modeling W2013 HLTH 340 Lecture A3 12

Pb ++

Cation transport channel (TRPV6) for calcium ion: absorption in the intestinal epithelium

porter channel anti ATP -dependent channel

W2013 HLTH 340 Lecture A3 13

Absorption pathways for lead permeation from the intestinal lumen through the enterocytes

TRPV6 (Ca ++ ) DMT-1 (Fe ++ ) ZIP-1 (Zn ++ )

paracellular transcellular ??

W2013 HLTH 340 Lecture A3 14

• • • • Lead (Pb): a heavy metal toxicant that is a common environmental health hazard 4 major toxic heavy metals are of common concern in environmental health – lead – – – mercury cadmium arsenic major environmental sources of lead – leaded paints (lead oxide PbO) -- houses built before 1978 – – – – auto exhaust in soils (PbCO 3

pica

from leaded gasoline) -- leaded gasoline additive (tetraethyl lead) until 1976 in young children (PbO in house dust, paint chips) lead contamination dust (industrial and lead smelter neighborhoods) lead drinking water pipes in older neighborhoods/houses chronic exposure to very low levels of lead (~10 ug/dL??) can cause permanent neurologic damage in children – IQ reduction and subtle mental retardation – hyperactivity and behavioral disorders (maybe??) prevention of chronic lead poisoning -- (1) infants (2) pregnant women (3) elderly – calcium supplements (BEWARE!) – – diet with dairy products, high protein intake, adequate vitamin D estrogen supplements in post-menopausal women??

W2013 HLTH 340 Lecture A3 15

Pathological features of lead poisoning in adults and children In the adult, the brain and central nervous system are relatively less vulnerable to the toxic effects of lead because the adult brain is biologically matured and does not undergo developmental retardation as is the case for infants and young children.

Therefore many adults may experience other health effects such as chronic anemia, hypertension, or kidney malfunction.

In children the main effect is neurological (impaired brain development).

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Speciation of lead (Pb) in the environment W2013 HLTH 340 Lecture A3 17

Causal pathways of lead exposure and health effects DPSEEA framework

D P S

“

stressor

”

E

“

exposure

”

E

“

effect

” W2013 HLTH 340 Lecture A3

A

18

Lead pipe replacement programs can lead to elevated lead in home drinking water supplies W2013 HLTH 340 Lecture A3 19

Effects of lead poisoning in children related to blood lead levels (ug/DL) W2013 HLTH 340 Lecture A3 20

Potential effect of chronic lead poisoning on the intellectual development of young children W2013 HLTH 340 Lecture A3 21

Effect of ethnicity (race) on percentage of children with blood lead conc > 10 ug/dL W2013 HLTH 340 Lecture A3 22

Relationship between population poverty and % living in high-risk housing for lead exposure W2013 HLTH 340 Lecture A3 23

Lead exposure patterns in neighborhoods close or distant to arterial roads W2013 HLTH 340 Lecture A3 24

W2013 Effect of phase-out of leaded gasoline in the 1970 ’ s (United States)

observed lead levels regulatory lead levels (ug/dL in blood)

HLTH 340 Lecture A3

< 2 ug/dL?

25