Induction of xenobiotic biotransformation by the insecticide chlordimeform, a metabolite 4-chloro-o-toluidine and a structurally related chemical o-toluidine.
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. Ethoxy-resorufin-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 50 mg/kg with chlordimeform and at 10 mg/kg with the other treatments. Chlordimeform increased the 7 alpha and 16 alpha androstenedione hydroxylase pathways. 4-Chloro-o-toluidine increased the 7 alpha, 16 beta and 16 alpha hydroxylase pathways, while o-toluidine increased the 7 alpha, 6 beta, 16 beta and 16 alpha 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.
Leslie
C
C
National Institute of Occupational Health and Safety, Westmead Hospital, University of Sydney, Australia.
Reidy
G F
GF
Murray
M
M
Stacey
N H
NH
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D002742:Chlorphenamidine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000096:biosynthesis; D014052:Toluidines / Q000494:pharmacology*
D000578:Amidines; D014052:Toluidines; C556393:p-chloro-o-toluidine hydrochloride; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; C023622:2-toluidine; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D002742:Chlorphenamidine