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IFM Environmental Health > Total Toxic Load and the Science of Biotransformation > Flashcards

Total Toxic Load and the Science of Biotransformation Flashcards

1
Q

Body burden

A

The quantity of an exogenous substance (eg
heavy metal or xenobiotic) or its metabolites that
accumulates in an individual

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2
Q

Total toxic load

A

The total body burdens of exogenous

chemicals, heavy metals and toxic endogenous compounds

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3
Q

demographic with highest odds ratio of >10 POPs in 90th percentile

A

non-hispanic blacks

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4
Q

Biotransformation definition

A

The phased metabolic conversion of
endogenous and xenobiotic chemicals into
more water-soluble compounds—facilitating
their elimination through urine and bile

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5
Q

Phase I reactions

A

Oxidation
Reduction
Hydrolysis

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6
Q

Cytochrome P450 enzymes - phase I or II

A

phase I

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7
Q

Phase II reactions

A
  • Glutathione conjugation
  • Amino acid conjugation
  • Methylation
  • Sulfation
  • Acetylation
  • Glucuronidation
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8
Q

P-Glycoprotein “Antiporter” Export Pump

A

Typically co-expressed & co-induced with CYP3A4 (gut wall)
• Decreases intracellular concentration of wide range of substrates
• Active in organs of absorption, distribution & elimination (for selfprotection)
• intestines
• blood-brain barrier (prevents chemicals from entering brain)
• kidneys
• liver (biliary)

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9
Q

Phase I reactions

A

Oxidation
Reduction
Hydrolysis

make it more polar

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10
Q

“multi-drug resistance” in chemo from

A

P-glycoprotein antiporter induction

e.g. St. John’s wort

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11
Q

grapefruit juice and berberine and others

A

P-Glycoprotein “Antiporter” Export Pump INHIBITED BY

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12
Q

CYP 450 enzyme in gut wall

A

Cyp 3a4

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13
Q

CYP-2D6 - what it catalyzes

A 
Catalyzes primary metabolism of
• Codeine (converts to morphine)
• Dextromethorphan (converts to detrorphan)
• Tamoxifen
• Many beta blockers
• Many tricyclic antidepressants, SSRIs
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14
Q

CYP-2D6 inhib

A 
SSRIs,
bupropion, 
quinidine, 
haloperidol, 
berberine
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15
Q

CYP-2D6 induced by

A

dexamethasone
rifampicin
glutethimide

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16
Q

tamoxifen

A

in low cyp 2d6 higher risk of breast ca recurrence

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17
Q

cyp that metab alcohol (ethanol)

A

CYP 2E1

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18
Q

coffee CYP

A

CYP1A2

highly inducible and 40x fold difference in genetics

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19
Q

why do smokers have high caffeine tol?

A

Cigarette smoking induces CYP1A2, (as does charbroiled

meat) which increases the rate of caffeine demethylation

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20
Q

CYP associated with increased risk of cancers of prostate &

breast; autoimmune disease (SLE, RA)

A

CYP-1B1

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21
Q

Mech of CYP 1B1

A

Catalyzes bioactivation of diverse range of pro-carcinogens
into genotoxic metabolites
• Oxidizes estrogen into 4-OH metabolites
• Induced by organochlorines (dioxin, PCBs), PAHs, benzopyrenes
(cigarette smoke), UV light (skin), indolocarbazole (I3C
metabolite)
• Xenoestrogens increase activity

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22
Q

SNPs higher in breast CA

A

(aromatase) and CYP1B1.

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23
Q

SNPs higher in non breast CA

A

higher levels of the protective enzymes COMT and

NQO1.

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24
Q

main carcinogenic estrogen metabolite:

A

4OHE2

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25
CYP450 Phenotypic Variability • Drug interactions: * Genetic polymorphisms * Age: * Inflammation: * Liver disease (esp cirrhosis)
-Activity can range from 5x in constitutive expression to 400x from drug interactions - SNPs can contribute to increased, decreased or null activity - age - highly variable in children; may decline with age - tends to decrease CYP-450 activity (highly variable) may decrease expression/action
26
CYP 450 system induced by nuclear receptors:
AhR, PXR, CAR, Vitamin D receptor
27
how does fasting alter detox
phase 1 | esp CYP2E1, CYP2B1/2)
28
CYP 3A4 inducers
rifampin phenytoin St. John's wort ``` Cigarette smoke: 1A1,1A2, 1B1 • Charbroiled beef: 1A2,1A2, 1B1 • Dioxins (TCDD): 1A1, 1A2, 1B1 • Ethanol, solvents: CYP2E1 • Quercitin: mild effect • Red wine (resveratrol) • Glucocorticoids (licorice root) • Anticonvulsants ```
29
red wine - how does it affect metab?
likely induces intestinal CYP3A4 & possibly p-glycoprotein pump
30
Xenobiotic Response Element (XRE)
• Exposure to xenobiotics triggers a stress response that can upregulate the expression of metabolizing enzymes\ upregulates phase I> II
31
Important receptors for XRE
Aryl hydrocarbon receptor (AhR): dioxin, PAH, PCBs • “Orphan” receptors include: • Pregnane X receptor (PXR) • Constitutive Androstane Receptor (CAR) • Peroxisome Proliferator Activated Receptors (PPAR) • Retinoid X Receptor (RXR): binds to other receptors
32
UGT
Phase II enzyme that adds Glucuronic acid: uridine-diphosphate-glucuronosyltransferases (UGT)
33
SULT
Phase II enzyme that addsSulfate: sulfonyltransferases (SULT)
34
GST
Phase II Glutathione: gluthathione-S-transferases (GST)
35
NAT
Phase II Acetate: N-acetyltransferases (NAT)
36
Phase II amino acids
taurine, glycine, glutamine GTG
37
COMT
Phase II enzyme that adds Methyl group: methyltransferases; (e.g. COMT)
38
“phase II workhorse,”
``` UGT! Glucuronidation biotransforming the bulk of substrates in ER near CYP 450 all tissues glucuronides excreted in bile ```
39
Gilbert’s syndrome SNP
UGT1A1 (glucuronidation)
40
Gilbert's subgroup that has lower glucuronidation | capacity of acetaminophen
UGT-1A6*2 allele
41
Phase II enzyme “scavengers”
SULfonyl-Transferases (SULT) | Play a greater role with very low substrate concentrations
42
SULT byproducts excreted in
urine
43
↑BP, migraines, A fib caused by what phase II issue
SULT1A inhibition effect increase monoamines also inhibit catecholamine deactivation
44
endocrine disruptors work partially by
inhib SULT
45
(NQO1)
a phase II "neutralizing" enzyme Neutralizes genotoxic quinone-catecholestrogens NAD(P)H:quinone oxidoreductase 1
46
SULFATION & GLUCURONIDATION substrates
Many drugs & xenobiotics (esp. phenolic compounds) many steroid hormones & the fat-soluble vitamins bile acids, bilirubin, some neurotransmitters
47
ACETYLATION & METHYLATION substrates
Many drugs & some xenobiotics (esp. metals/ minerals) | many neurotransmitters
48
AMINO ACID (PEPTIDE) CONJUGATION substrates
Some drugs & xenobiotics (esp. aliphatic compounds) | fatty acids & bile acids
49
GLUTATHIONE CONJUGATION substrates
Few drugs but many xenobiotics (esp. toxic metals) | small carbon molecules, prostaglandins, and lipid peroxides
50
steroid hormones and fat-soluble vit metab by
sulfation and glucuronidation
51
bile acids metab by
sulfation/gluc | amino acid conj
52
only few drugs metab by
glutathione
53
small carbons, pg and lipid perox metab by
glutathione
54
Inducers of Phase II activity (UGT, GST, NQO1)
Nrf2/ARE
55
Antioxidant Response Element (ARE)
* DNA binding site that primarily activates phase II enzymes (minor effect on phase I) plus numerous other cytoprotective enzymes * ARE genes are activated by Nrf2
56
ARE inducers
Sulforaphane curcumin alpha lipoic acid oltipraz & BHA via Nrf2 activation2-4 • This mechanism may explain many observed beneficial effects of detoxifying phytochemicals 2-4
57
Nrf2
activates ARE (antioxidant response element) • Nrf2 transcription declines with age - This effect can be attenuated by phytochemicals & alpha lipoic acid
58
Why is phase II detox important?
Induction of these (phase II) genes reduces susceptibility to carcinogens, ROS, and other forms of chemical and physical toxicity.
59
colon cancer risk increased with which snps ?
NAT2 (upreg) CYP1A2 (upreg) smoking red meat charred
60
CYP1A1 & NAT-2 Polymorphisms | in Systemic Sclerosis & Lupus
slower NAT in SLE higher CYP 1a1 in SLE xneobiotics not metab and become reactive intermediates?
61
codeine snp
CYP 2D6 | phenotypic variability! absent/low in ~10% of cauc and blacks

IFM Environmental Health (6 decks)

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