Metabolism of vinyltoluene in the rat: effect of induction and inhibition of the cytochrome.

Metabolism of vinyltoluene was studied in rats after injecting different doses of vinyltoluene. The main metabolites excreted in urine of rats after vinyltoluene treatment were: thioethers, p- methylmandelic acid, p- methylphenylglyoxylic acid, p- methylbenzoyl glycine, p- methylphenylacetyl glycine and p- vinylbenzoyl glycine. The highest excretion rate was obtained with doses of 50, 250 and 500 mg/kg already within the first six ours. However, the dose of 500 mg/kg did not increase the excretion rates of these metabolites compared to the dose of 250 mg/kg suggesting that the metabolic pathways begin to be saturated with the amount of 250 mg/kg. At the dose of 50 mg/kg 55% of the dose was detected as urinary metabolites within 23 hr, mainly within the first 6 hr. The amounts of the excreted metabolites expressed as per cent of the injected dose (250 mg/kg or 500 mg/kg) were lower than that caused by 50 mg/kg, and a noticeable amount of the total sums were excreted within 11-23 hr suggesting that the excretion was still continued with the doses of 250 and 500 mg/kg 23 hr after the injection. The excretion of all analyzed metabolites of vinyltoluene was prevented by the pretreatment of the rats with 1- phenylimidazole , an inhibitor of cytochrome P-450 monoxygenases. This indicates that these metabolites were formed as catalyzed by cytochrome P-450. The structures of the analyzed metabolites suggest that the main reactive intermediate of vinyltoluene is vinyltoluene-7,8-oxide. Furthermore, the amounts of the excreted metabolites showed that the main detoxification pathways of v inyltoluene -7,8-oxide were the conjugation with reduced glutathione and hydration to diols. Pre-treatment of the rats with PCBs increased the excretion rates of the metabolites. However, the PCB-pretreated rats excreted less thioethers (62%) compared to the rats treated only with the same amount of vinyltoluene whereas the total sum of the other metabolites was about the same in these both groups. This result suggests that PCBs change the metabolism of vinyltoluene to some other pathway which could be glucuronide conjugation because PCBs increased the activity of UDP glucuronosyltransferase in a dose-dependent manner.