Induction of xenobiotic biotransformation by the insecticide chlordimeform, a metabolite 4-chloro- o-toluidine and a structurally related chemical o-toluidine

Abstract

Chlordimeform, 4-chloro- o-toluidine and o-toluidine have all been found to have carcinogenic properties. Due to an empirical link between such properties and alteration of some biotransformation enzymes, the abilities of these three chemicals to affect cytochrome P-450 mediated biotransformation, epoxide hydrolase and glutathione S-transferase have been examined. Chlordimeform had no effect on the cytochrome P-450 content, aniline p-hydroxylase or glutathione S-transferase activities, but induced ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase and epoxide hydrolase activities and decreased aldrin epoxidase and aminopyrine N-demethylase activities. The metabolite 4-chloro- o-toluidine increased cytochrome P-450, ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase, glutathione S-transferase and epoxide hydrolase activities. o-Toluidine induced cytochrome P-450, ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase, and aldrin epoxidase activities. Ethoxyresorufin- O-deethylase activity was induced approximately eight times by Chlordimeform and 18 times by 4-chloro- o-toluidine and o-toluidine. Induction was seen at 50mg/kg with Chlordimeform and at 10 mg/kg with the other treatments. Chlordimeform increased the 7α and 16α androstenedione hydroxy-lase pathways. 4-Chloro- o-toluidine increased the 7α, 16β and 16α hydroxylase pathways, while o-toluidine increased the 7α, 6β, 16β and 16α hydroxylase pathways. All three chemicals marginally decreased the testosterone pathways. SDS-PAGE of rat microsomes revealed an increase in a protein band of MW c54,000 for the Chlordimeform and 4-chloro- o-toluidine treated groups. Taken together with the increase in ethoxyresorufin- O-deethylase activity these observations are consistent with the induction of hepatic isozyme P-450d. Thus each chemical has been shown to induce various pathways of biotransformation with increases in the P-450c and P-450d specific substrate ethoxyresorufin- O-deethylase being a consistent finding.