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Section C
Factors Affecting Biotransformation
Factors that Affect
Xenobiotic Biotransformation
w  Species, strain, and genetic variations
–  Risk assessment is often based on
responses observed in animals
–  In this regard, there are often
significant differences between species
in their abilities to metabolize
xenobiotics
Continued 27
Factors that Affect
Xenobiotic Biotransformation
–  Likewise, even within a species,
including man, there are differences
–  The basis of such differences is often
genetic (polymorphisms)
28
Examples of Factors that Affect
Xenobiotic Biotransformation
w  Species, strain, and genetic variation
- Hexobarbital
–  Aflatoxin B1
–  Benzo[a]pyrene 7,8 –dihydrodiol
–  Isoniazid
w  Age
w  Diet
w  Exposure to other chemicals
29
Species Differences in the Duration of
Action and Metabolism of Hexobarbital
Species
Mouse
Rabbit
Rat
Dog
Duration of
Action
Relative Enzyme
Activity
(Sleeping time, min)
(µg hexobarbitol
metabolized/gm/liver/hr)
12 ± 8
49 ± 12
90 ± 15
315 ± 105
598 ± 184
196 ± 28
134 ± 51
36 ± 30
Source: G.P. Quinn, et.al. Species, Strain and Sex Differences in the Metabolism of
Hexobarbital, Aminopyrine and Aniline. Biochem. Pharmacol. 1:152, 1958
30
Species, Strain,
and Genetic Variation
Continued 31
Species, Strain,
and Genetic Variation
32
His+ revertants/mg
Metabolism of Aflatoxin B1
and Benzo[a]pyrene
4000
A
B
3000
2000
1000
A B CDE FG H I J
A B CDE FG H I J
Biopsy samples
Inter-individual differences in the metabolism of aflatoxin B1 (A)
and benzo[a]pyrene 7,8-dihydrodiol (B) to mutagens( assessed
by Ames test) by microsomes from samples of human liver
33
obtained during abdominal surgery
The Bimodal Distribution of Patients into
Those who Rapidly Inactivate Isoniazid and
Those who Slowly Metabolize It
Number of Patients
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9 10 11 12
Plasma Isoniazid ( µg/mL)
34
Age as Affecting Xenobiotic
Biotransformation
Birth
Puberty
Adult
Elderly (>65 yrs)
Age
Schematic representation of the ontogeny of
hepatic drug metabolic activity
35
Diet as Affecting Xenobiotic
Biotransformation
36
Exposure to Other Chemicals
37