PRINCIPLES OF TOXICOLOGY

pyridoxal phosphate depletion by the unmetabolized isoniazid. Slow acetylators have an increased risk
of developing bladder cancer when exposed to arylamine compounds but are less represented than the
overall population among colorectal cancer patients.
Recently much attention has been directed at the number of isozymes, of human cytochrome P450
since variations in the amounts of the various isozymes that have some degree of substrate selectivity,
could explain the variations in responses observed to standard doses of drugs. It could also partly
explain the susceptibility of certain individuals to toxicity by chemicals that are bioactivated via
oxidative metabolism. The cytochrome P450 2D6 polymorphism divides the Caucasian population
into poor (5–10 percent) and extensive metabolizers of over 40 drugs and has been implicated in the
development of some forms of cancer. Interestingly, extensive metabolizers are overrepresented in
tobacco-smoke-associated lung cancer patients and underrepresented in leukaemia and melanoma
patients. Polymorphism in the 2C19 form shows interracial differences, with an incidence of poor
metabolizers of > 5 percent in Caucasian populations and 20 percent in Asian populations, although
to date such differences have not been implicated in toxicities other than those arising from the slow
metabolism of drugs.
Gender Although there is no evidence of major gender differences in hepatic xenobiotic metabolism
in humans, a major difference has been well documented for rats, particularly with respect to
cytochrome P450. (Limited studies in humans suggest that females have slightly greater oxidative
metabolism rates than do males.) It is also well documented that there is gender-dependent expression
of certain cytochrome P450 isozymes in the rat (see Table 3.4). Sex differences would appear to be
independent of the strain of rat and also apparently occur in at least one other rodent species, the
hamster (Table 3.9).
The mouse generally displays a higher cytochrome P450 concentration and activity in females.
Phase II conjugations can also show sex differences, and these, like cytochrome P450, may be isozyme
specific. Most of the gender-related differences in cytochrome P450 expression in rodents have been
related to gender differences in growth hormone secretion.
Although small differences are evident, the effects of inducers are similar between sexes of a
species. From the examples given in Table 3.9, the phenobarbital-induced increases in cytochrome
P450, glutathione S-transferase, and preferential increase in GT2 UDP-glucuronosyltransferase activity
over GT1 UDP-glucuronosyltransferase activity are similar in males and females of both hamster
and rat. Similarly, phenobarbital does not increase sulfotransferase activity in either sex of either
species.
TABLE 3.9 Gender Differences in Xenobiotic-Metabolizing Enzymes a
3.2 BIOTRANSFORMATION REACTIONS 81
Phase I Phase II
Species and
pNA UGT
Status Strain/Gender P450 deM GT1 GT2 GST ST
(Female vs. Male)
Naive Rat: SD 0.85 0.75 0.70 1.00 1.05 0.30
Rat: Fischer 0.70 0.85 0.35 0.90 1.15 —
Hamster 0.90 0.80 0.80 0.80 1.00 0.85
(Induced vs. Naive)
Phenobarbital-induced Rat: SD male 2.35 6.60 1.25 4.20 2.10 1.05
Rat: SD female 1.65 3.75 1.50 3.30 1.55 0.90
Hamster: male 1.60 3.26 1.20 2.20 1.20 0.80
Hamster: female 1.40 3.35 1.30 1.95 1.15 0.60
a Abbreviations: pNA deM = p-nitroanisole demethylase; UGT = UDPglucuronosyltransferase (two isozymes: GT1 and GT2);
GST = glutathione S-transferase; ST = sulfotransferase; SD = Sprague–Dawley.