Effects of buthiobate, a fungicide, on cytochrome P-450 of rat liver microsomes.
Effects of buthiobate (S-butyl S'-p-tert-butylbenzyl N-3-pyridyldithiocarbonimidate), a fungicide which inhibits lanosterol 14 alpha-demethylation catalyzed by a cytochrome P-450 (P-450 14DM) of yeast, on cytochrome P-450 of rat liver microsomes were studied. Buthiobate bound to limited forms of cytochrome P-450 in the microsomes with three different Kd values, 0.38, 1.56 and 13.6 microM. Buthiobate inhibited lanosterol 14 alpha-demethylase activity of the microsomes with a 50%-inhibition concentration of 0.4 microM. This concentration was comparable to the lowest Kd of buthiobate for the microsomal cytochrome P-450 and also to the 50%-inhibition concentration of the inhibitor for lanosterol 14 alpha-demethylation by yeast P-450 14DM. Buthiobate partially inhibited 7-ethoxycoumalin O-deethylase activity of the microsomes but inhibited neither benzphetamine N-demethylation nor p-nitroanisole O-demethylation. These observations suggest that cytochrome P-450s catalyzing drug oxidations are rather insensitive to buthiobate. These observations indicate that buthiobate is an unique inhibitor for hepatic microsomal cytochrome P-450 system, which inhibits cholesterol biosynthesis effectively but causes a little effect on drug oxidations.
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005659:Fungicides, Industrial / Q000494:pharmacology*; D007096:Imidoesters / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D058886:Sterol 14-Demethylase
C548417:Cyp51 protein, rat; D005659:Fungicides, Industrial; D007096:Imidoesters; C016349:buthiobate; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase