Download 09/15/06

Metabolism Biotransformation
Supplementary readings:
Casarett and Doull,Chapter 6
Timbrell, Chapters 4 and 5
Non-polar Hydrophobic
(lipophilic)
Solubility in water
XENOBIOTIC
Phase I Metabolism
Oxidation
Can accumulate in tissues
INTERMEDIATE METABOLITE
Phase II Metabolism
Conjugation
May be reactive/toxic
WATER-SOLUBLE METABOLITE
Lipophobic Hydrophilic
(Polar)
ELIMINATION
What is a xenobiotic ?
Phase I reactions
• Chemical modification of xenobiotics
• Introduces or uncovers polar functional
groups that provide sites for Phase II
metabolism
• Major classes of reaction:
– Oxidation
– Reduction
– Hydrolysis
Overview of oxidations,
reductions, hydrolyses
• Oxidation
–Loss of electrons M M+ + e–Gain of oxygen R + O RO
Oxidation reactions
OH
Benzene
Phenol
Hydroxylation
Epoxidation
HC
O
HC
CH2
Styrene
CH2
Styrene oxide
H
O
H
Benzo[a]pyrene
Benzo[a]pyrene
7,8-oxide
Overview of oxidations,
reductions, hydrolyses
• Reduction
– Gain of electrons M+ + e- M
– Loss of oxygen RO R + O
– Gain of hydrogen R + H RH
Reduction
• Nitro to amino group
NO2
NO
HNOH
• Chromium VI to Chromium III
Cr6+ + 3 e-
Cr3+
H NH
Hydrolysis
• Addition of water
– Cleavage of R-O or R-N bond accompanied
by addition of H2O
R’-O-R + H2O
R’-N-R + H2O
H
R’-O-H + R-OH
R’-N-H + R-OH
H
Principal Phase I enzymes
•
•
•
•
•
•
•
Cytochrome P450
Flavin monooxygenase
Monoamine oxidase
Esterases
Amidases
Hydrolases
Reductases, dehydrogenases, oxidases
Flavin monooxygenase
• Flavoprotein
• Mixed-function amine oxidase
• Located in smooth endoplasmic reticulum,
in human, pig, rabbit liver, guinea-pig lung,
human kidney
• Uses NADPH as a source of reducing
equivalents
• Not inducible
Overall reaction
R-H + O2 + NADPH + H+
R-OH + H2O + NADP+
Monoamine oxidase
• Metabolizes endogenous monoamine
neurotransmitters
• Uses NADPH as a source of reducing
equivalents
• Found in the endoplasmic reticulum and in
mitochondria, of nerve endings and liver
Esterases
• Hydrolyse esters to carboxylic acid and alcohol
functional groups
• Non-specific esterases in plasma, more
substrate-specific forms in liver cytosol
O
O
C
H3C
O
H2
C
Ethyl acetate
+ H2O
CH3
H2
C
C
H3C
OH
Acetic acid
+
HO
CH3
Ethanol
Amidases
• Hydrolyse amides to carboxylic acids and
amines (or ammonia)
• Found in plasma and in liver cytosol
O
H
R
C
N
H
O
+ H2O
R
H
+
C
OH
H
N
H
Hydrolases
• Hydrolyse ethers
H2
C
H3C
H2
C
O
Diethyl ether
H2
C
+ H2O
CH3
H3C
H2
C
OH
Ethanol
+
HO
Ethanol
CH3
Reductases, dehydrogenases,
oxidases
• In cytosol, endoplasmic reticulum,
mitochondria
Alcohol dehydrogenase
H
H3C
C
Aldehyde dehydrogenase
NAD+ NADH + H+
OH
H3C
O
NAD+ NADH + H+
C
H3C
H
O
C
OH
H
Ethanol
Acetaldehyde
Acetic acid
Cytochrome P450
• Heme protein
• Terminal oxidase of the mixed-function
oxidase (MFO) electron-transfer system
• Located in the smooth endoplasmic
reticulum of all major organs and
tissues
• Uses NADPH as a source of reducing
equivalents
• Inducible