Metabolism of Cyanox in rat. II. Sex-related differences in oxidative dearylation and desulphuration

Abstract

1. To examine the metabolites of Cyanox (O-4-cyanophenyl O, O-dimethyl phosphorothioate, cyanophos, CYAP) in brain, liver, blood cells and plasma during the early toxic period, the male and female rat was administered a single oral dose of [phenyl-¹⁴C]Cyanox at dose levels of 50 mg/kg and killed 5, 10 and 20 min thereafter. 2. Sex-related differences in the concentrations of metabolites were observed. Cyanoxon, produced by oxidative desulphuration, was observed in the brains of both sexes at all time points, but the concentrations were 2-6times higher in the male. The same metabolite was detected in the liver, blood cells and plasma of the male but not the female. The total concentrations of oxidative dearylation metabolites (4-cyanophenol +4-cyanophenylsulphate + glucuronide of 4-cyanophenol) in plasma, blood cell, brain and liver were larger in the male at all time points than those in the female, whereas the reverse was the case for demethylated metabolites (desmethylcyanox + desmethylcyanoxon) in all tissues except for the brain. 3. Studies of the in vitro metabolism of Cyanox revealed no sex-related difference for hepatic cytosolic fractions in terms of the major in vitro metabolic reaction, demethylation. On the other hand, the major reactions in microsomal fractions, oxidative desulphuration and oxidative dearylation, were significantly (2-3 times) greater in the male than in the female. 4. Oxidative desulphuration and oxidative dearylation, involving cytochrome P450 enzymes,were inhibited by male-specific ratCYP2C11 antiserum. The degreeof inhibition was more pronounced in the male case. Thus, the results strongly suggest that the 2C family of cytochrome P450 (male, CYP2C11 and CYP2C13; female, CYP2C12) contributes to oxidative desulphuration and dearylation of cyanox in the rat and that the activity of male-specific CYP2C11 (and CYP2C13) is greater than that of female-specific CYP2C12. The consequent greaterformation of cyanoxonin the male is consistent with the higher toxicity in this sex.