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Biotransformation Xenobiotic metabolism. “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6. CYP2A1 6  -OH CYP3A 6  -OH. Biotransformation. Water soluble xenobiotics are easier to eliminate ( t 1/2 ) Urine, feces but not exhalation

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biotransformation xenobiotic metabolism

BiotransformationXenobiotic metabolism

“Essentials of Toxicology”

by Klaassen Curtis D. and Watkins John B Chapter 6

biotransformation

CYP2A1 6-OH

CYP3A 6-OH

Biotransformation
  • Water soluble xenobiotics are easier to eliminate ( t1/2)
    • Urine, feces but not exhalation
    • If within barrier, no out
  • Multiple enzymes (families)
    • Constitutively expressed
    • Inducible
    • Broad specificity
    • Polymorphic (allelic variants)
    • Stereo-isomer specificity: 6-OH in hormones:
biotransformation1
Biotransformation

Relatively harmless

Potentially toxic xenobiotic

Metabolic activation

Detoxification

Inactive metabolite

Reactive intermediate

converting lipophilic to water soluble compounds
Converting lipophilic to water soluble compounds

Lipophilic

(non-polar)

Xenobiotic

Phase I - Activation

Reactive intermediate

Phase II - Conjugation

Conjugate

Water soluble

(polar)

Excretion

phase i
Phase I
  • introduction of functional group
  • hydrophilicity increases slightly
  • may inactivate or activate original compound
  • major player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)H
  • location of reactions is smooth endoplasmic reticulum
phase ii
Phase II
  • conjugation with endogenous molecules

(GSH, glycine, cystein, glucuronic acid)

  • hydrophilicity increases substantially
  • neutralization of active metabolic intermediates
  • facilitation of elimination
  • location of reactions is cytoplasm
phase i reactions

O

C C

C

O

Phase I reactions

Table 6.1

  • Oxidation
    • Hydroxylation (addition of -OH group)
    • N- and O- Dealkylation (removal of -CH side chains)
    • Deamination (removal of -NH side chains)
    • Epoxidation (formation of epoxides)
    • Oxygen addition (sulfoxidation, N-oxidation)
    • Hydrogen removal
  • Reduction
    • Hydrogen addition (unsaturated bonds to saturated)
    • Donor molecules include GSH, FAD, NAD(P)H
    • Oxygen removal
  • Hydrolysis
    • Splitting of C-N-C (amide) and C-O-C (ester) bonds

epoxide

See also Chapter 6 of Casarett and Doull’s “Toxicology”

biotransformation2
Biotransformation
  • Activation of xenobiotics is a key element

(e.g. benzene, vinyl chloride)

    • Reactive intermediates include epoxides and free radical species (unpaired electrons) that are short-lived and hence highly reactive
    • Protection is provided by
      • endogenous antioxidant substances, e.g. GSH
      • vitamins C and E
      • antioxidant enzymes, SOD, GPX, CAT in coupled reactions
    • Antioxidant molecules are oxidized in the process but have the capacity to regenerate the reduced form from the oxidized - NAD(P)H is a key player

See also p. 40-44 of Casarett and Doull’s “Toxicology”

cytochrome p450 cyp mixed function oxidases mfo
Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)
  • Located in many tissues but highly in liver ER
  • Human: 16 gene families
  • CYP 1,2,3 perform drug metabolism
  • >48 genes sequenced
  • Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
  • Highly inducible
    • Alcohol CYP2E1
    • Dioxin/PCBs CYP1A
    • Barbiturates CYP2B
  • CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)
metabolic enzymes
Metabolic enzymes
  • Microsomal:
    • CYP450 monooxygenases
    • Flavin monooxygenase
  • Non-microsomal
    • Alcohol dehydrogenase
    • Aldehyde dehydrogenase
    • Monoamine and diamine oxidases
  • Both
    • Esterases and Amidases
    • Prostaglandin synthase
    • Peroxidases
slide13

Cooxidation of acetaminophen

by prostaglandin endoperoxide synthetase

Compare to fig. 6-2

slide20

Stereoselective

hydroxylation

slide23

Ready for elimination

reabsorption

Intestinal flora as part of biotransformation

Flora action

slide29

Flavin mono-oxygenases

(FMO) catalyzed reactions

Nitrogen compounds

phase ii reactions
Phase II reactions
  • Glycoside conjugation - glucuronidation
  • Sulfate - sulfation
  • Glutathione (GSH)
  • Methylation
  • Acylation
    • Acetylation
    • Amino acid conjugation
    • Deacetylation
  • Phosphate conjugation
glutathione
Glutathione

-glutamyl-cysteinyl-glycine

Active site of a GST:

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