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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


CYP2A1 6-OH



  • 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:


Relatively harmless

Potentially toxic xenobiotic

Metabolic activation


Inactive metabolite

Reactive intermediate

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




Phase I - Activation

Reactive intermediate

Phase II - Conjugation


Water soluble



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





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


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


  • 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

Cooxidation of acetaminophen

by prostaglandin endoperoxide synthetase

Compare to fig. 6-2



Metabolism of benzo(a)pyrene to 9,10 epoxide:

Potent mutagen that binds DNA

Ready for elimination


Intestinal flora as part of biotransformation

Flora action

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



Active site of a GST: