Biotransformation
Biotransformation
Biotransformation
Xenobiotic metabolism
“Essentials of Toxicology”
by Klaassen Curtis D. and Watkins John B
Chapter 6
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:
CYP2A1 6-OH
CYP3A 6-OH
Biotransformation
Metabolic
Detoxification activation
Reactive intermediate
Phase II - Conjugation
Conjugate
Water soluble
Excretion (polar)
Phase I
Oxidation
Hydroxylation (addition of -OH group)
N- and O- Dealkylation (removal of -CH side chains)
Deamination (removal of -NH side chains) O epoxide
Epoxidation (formation of epoxides) C C
Oxygen addition (sulfoxidation, N-oxidation)
Hydrogen removal
Reduction
Hydrogen addition (unsaturated bonds to saturated)
Donor molecules include GSH, FAD, NAD(P)H
Oxygen removal
C O
Hydrolysis
Splitting of C-N-C (amide) and C-O-C (ester) bonds
G
(B)
D
Oxidation of vinyl chloride to an
epoxide
Metabolic enzymes
1. Microsomal:
1. CYP450 monooxygenases
2. Flavin monooxygenase
2. Non-microsomal
1. Alcohol dehydrogenase
2. Aldehyde dehydrogenase
3. Monoamine and diamine oxidases
3. Both
1. Esterases and Amidases
2. Prostaglandin synthase
3. Peroxidases
Cooxidation of
acetaminophen
by prostaglandin
endoperoxide
synthetase
n Flora action
tio
r p
o
a bs
re
Oxidation reactions
Benzene trasformation to
leukemia-causing metabolite
Flavin mono-oxygenases
(FMO) catalyzed reactions
Nitrogen compounds
Phase II reactions
• Glycoside conjugation - glucuronidation
• Sulfate - sulfation
• Glutathione (GSH)
• Methylation
• Acylation
– Acetylation
– Amino acid conjugation
– Deacetylation
• Phosphate conjugation
Glucuronidation of phenol
Sulfation of phenol and toluene
GSH conjugation of
acetaminophen
Glutathione
-glutamyl-cysteinyl-glycine