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.