Effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on drug metabolizing activity in rat liver microsomes.
The effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on drug metabolizing activity in rat liver microsomes was examined. Malotilate (500 mg/kg/day) was administered orally to rats for 3 days. The contents of cytochrome P-450 (P-450) and cytochrome b5 (b5), the activity of NADPH-cytochrome c reductase, and the metabolization of aniline, aminopyrine, benzo(a)pyrene (B(a)P) and 7-ethoxycoumarin (7-EC) in the microsomal fraction were examined 24 hr after the final administration of malotilate. The content of b5 and the activity of NADPH-cytochrome c reductase were increased by the malotilate treatment, but the content of P-450 was not significantly affected. 7-EC O-deethylation was markedly and aminopyrine N-demethylation was moderately enhanced; in contrast, aniline hydroxylation was significantly and B(a)P hydroxylation was slightly reduced. Such different effects of malotilate among the four substrate-metabolizing activities may be due mainly to the increase in the content of b5, which participates in the transport of the second electron required for P-450 function to various extents. It is also possible that malotilate affects the population of P-450 subtypes, each having a different substrate specificity and a different affinity for b5.
D000632:Aminopyrine / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000814:Aniline Compounds; D003374:Coumarins; D003580:Cytochromes; D008314:Malonates; D004364:Pharmaceutical Preparations; D000632:Aminopyrine; C017299:7-ethoxycoumarin; D001564:Benzo(a)pyrene; D009251:NADPH-Ferrihemoprotein Reductase; C024808:diisopropyl 1,3-dithiol-2-ylidenemalonate; C023650:aniline