PRINCIPLES OF TOXICOLOGY - Biology East Borneo

3.2 BIOTRANSFORMATION REACTIONS 81pyridoxal phosphate depletion by the unmetabolized isoniazid. Slow acetylators have an increased riskof developing bladder cancer when exposed to arylamine compounds but are less represented than theoverall population among colorectal cancer patients.Recently much attention has been directed at the number of isozymes, of human cytochrome P450since 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 partlyexplain the susceptibility of certain individuals to toxicity by chemicals that are bioactivated viaoxidative metabolism. The cytochrome P450 2D6 polymorphism divides the Caucasian populationinto poor (5–10 percent) and extensive metabolizers of over 40 drugs and has been implicated in thedevelopment of some forms of cancer. Interestingly, extensive metabolizers are overrepresented intobacco-smoke-associated lung cancer patients and underrepresented in leukaemia and melanomapatients. Polymorphism in the 2C19 form shows interracial differences, with an incidence of poormetabolizers of > 5 percent in Caucasian populations and 20 percent in Asian populations, althoughto date such differences have not been implicated in toxicities other than those arising from the slowmetabolism of drugs.Gender Although there is no evidence of major gender differences in hepatic xenobiotic metabolismin humans, a major difference has been well documented for rats, particularly with respect tocytochrome P450. (Limited studies in humans suggest that females have slightly greater oxidativemetabolism rates than do males.) It is also well documented that there is gender-dependent expressionof certain cytochrome P450 isozymes in the rat (see Table 3.4). Sex differences would appear to beindependent of the strain of rat and also apparently occur in at least one other rodent species, thehamster (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 isozymespecific. Most of the gender-related differences in cytochrome P450 expression in rodents have beenrelated to gender differences in growth hormone secretion.Although small differences are evident, the effects of inducers are similar between sexes of aspecies. From the examples given in Table 3.9, the phenobarbital-induced increases in cytochromeP450, glutathione S-transferase, and preferential increase in GT2 UDP-glucuronosyltransferase activityover GT1 UDP-glucuronosyltransferase activity are similar in males and females of both hamsterand rat. Similarly, phenobarbital does not increase sulfotransferase activity in either sex of eitherspecies.TABLE 3.9 Gender Differences in Xenobiotic-Metabolizing Enzymes aPhase IPhase IISpecies andpNA UGTStatus Strain/Gender P450 deM GT1 GT2 GST ST(Female vs. Male)Naive Rat: SD 0.85 0.75 0.70 1.00 1.05 0.30Rat: 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 1.05Rat: SD female 1.65 3.75 1.50 3.30 1.55 0.90Hamster: male 1.60 3.26 1.20 2.20 1.20 0.80Hamster: female 1.40 3.35 1.30 1.95 1.15 0.60a Abbreviations: pNA deM = p-nitroanisole demethylase; UGT = UDPglucuronosyltransferase (two isozymes: GT1 and GT2);GST = glutathione S-transferase; ST = sulfotransferase; SD = Sprague–Dawley.