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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
Q

CYP450 Phenotypic Variability
• Drug interactions:

  • Genetic polymorphisms
  • Age:
  • Inflammation:
  • Liver disease (esp cirrhosis)
A

-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
Q

CYP 450 system induced by nuclear receptors:

A

AhR, PXR, CAR, Vitamin D receptor

27
Q

how does fasting alter detox

A

phase 1

esp CYP2E1, CYP2B1/2)

28
Q

CYP 3A4 inducers

A

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
Q

red wine - how does it affect metab?

A

likely induces intestinal CYP3A4 & possibly p-glycoprotein pump

30
Q

Xenobiotic Response Element (XRE)

A

• Exposure to xenobiotics triggers a stress response that can upregulate the expression of metabolizing enzymes\
upregulates phase I> II

31
Q

Important receptors for XRE

A

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
Q

UGT

A

Phase II enzyme that adds Glucuronic acid: uridine-diphosphate-glucuronosyltransferases
(UGT)

33
Q

SULT

A

Phase II enzyme that addsSulfate: sulfonyltransferases (SULT)

34
Q

GST

A

Phase II Glutathione: gluthathione-S-transferases (GST)

35
Q

NAT

A

Phase II Acetate: N-acetyltransferases (NAT)

36
Q

Phase II amino acids

A

taurine, glycine, glutamine

GTG

37
Q

COMT

A

Phase II enzyme that adds Methyl group: methyltransferases; (e.g. COMT)

38
Q

“phase II workhorse,”

A 
UGT!
Glucuronidation 
 biotransforming the bulk of substrates
in ER near CYP 450
all tissues
glucuronides excreted in bile
39
Q

Gilbert’s syndrome SNP

A

UGT1A1 (glucuronidation)

40
Q

Gilbert’s subgroup that has lower glucuronidation

capacity of acetaminophen

A

UGT-1A6*2 allele

41
Q

Phase II enzyme “scavengers”

A

SULfonyl-Transferases (SULT)

Play a greater role with very low substrate concentrations

42
Q

SULT byproducts excreted in

43
Q

↑BP, migraines, A fib caused by what phase II issue

A

SULT1A inhibition effect
increase monoamines
also inhibit catecholamine deactivation

44
Q

endocrine disruptors work partially by

A

inhib SULT

45
Q

(NQO1)

A

a phase II “neutralizing” enzyme
Neutralizes genotoxic quinone-catecholestrogens
NAD(P)H:quinone oxidoreductase 1

46
Q

SULFATION & GLUCURONIDATION substrates

A

Many drugs & xenobiotics (esp. phenolic compounds)
many steroid hormones & the fat-soluble vitamins
bile acids, bilirubin, some neurotransmitters

47
Q

ACETYLATION & METHYLATION substrates

A

Many drugs & some xenobiotics (esp. metals/ minerals)

many neurotransmitters

48
Q

AMINO ACID (PEPTIDE) CONJUGATION substrates

A

Some drugs & xenobiotics (esp. aliphatic compounds)

fatty acids & bile acids

49
Q

GLUTATHIONE CONJUGATION substrates

A

Few drugs but many xenobiotics (esp. toxic metals)

small carbon molecules, prostaglandins, and lipid peroxides

50
Q

steroid hormones and fat-soluble vit metab by

A

sulfation and glucuronidation

51
Q

bile acids metab by

A

sulfation/gluc

amino acid conj

52
Q

only few drugs metab by

A

glutathione

53
Q

small carbons, pg and lipid perox metab by

A

glutathione

54
Q

Inducers of Phase II activity (UGT, GST, NQO1)

55
Q

Antioxidant Response Element (ARE)

A
  • 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
Q

ARE inducers

A

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
Q

Nrf2

A

activates ARE (antioxidant response element)
• Nrf2 transcription declines with age - This effect can be
attenuated by phytochemicals & alpha lipoic acid

58
Q

Why is phase II detox important?

A

Induction of these (phase II) genes
reduces susceptibility to carcinogens,
ROS, and other forms of chemical and
physical toxicity.

59
Q

colon cancer risk increased with which snps ?

A

NAT2 (upreg)
CYP1A2 (upreg)
smoking
red meat charred

60
Q

CYP1A1 & NAT-2 Polymorphisms

in Systemic Sclerosis & Lupus

A

slower NAT in SLE
higher CYP 1a1 in SLE

xneobiotics not metab and become reactive intermediates?

61
Q

codeine snp

A

CYP 2D6

phenotypic variability! absent/low in ~10% of cauc and blacks

IFM Environmental Health (6 decks)

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