PT  - JOURNAL ARTICLE
AU  - Eiji Kashiyama
AU  - Tsuyoshi Yokoi
AU  - Masaaki Odomi
AU  - Yoshihiko Funae
AU  - Kazuaki Inoue
AU  - Tetsuya Kamataki
TI  - CYTOCHROME P450 RESPONSIBLE FOR THE STEREOSELECTIVE<em>S</em>-OXIDATION OF FLOSEQUINAN IN HEPATIC MICROSOMES FROM RATS AND HUMANS
DP  - 1997 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 716--724
VI  - 25
IP  - 6
4099  - http://dmd.aspetjournals.org/content/25/6/716.short
4100  - http://dmd.aspetjournals.org/content/25/6/716.full
SO  - Drug Metab Dispos1997 Jun 01; 25
AB  - The forms of cytochrome P450 involved in the stereoselectiveS-oxidation of flosequinan [(±)-7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone] were investigated in vitro using liver microsomes from rats and humans. Rat liver microsomes supplemented with NADPH catalyzed the four different S-oxidations, which were from flosequinan sulfide (FS; 7-fluoro-1-methyl-3-methylthio-4-quinolone) to R(+)- and S(−)-flosequinan (R-FSO andS-FSO, respectively) and from R-FSO andS-FSO to flosequinan sulfone (FSO2; 7-fluoro-1-methyl-3-methylsulfonyl-4-quinolone). The activities of all the S-oxidases in liver microsomes from male rats were higher than those from female rats. The activities of theS-oxidases measured at a high substrate concentration (1 mM) were induced by treatment of rats with phenobarbital and dexamethasone. Treatment of rats with 3-methylcholanthrene also induced the activities, but only at a low substrate concentration (50 μM), except for the S-oxidase catalyzing the reaction from FS toR-FSO. Enzymes induced by clofibrate and ethanol were not involved in the oxidations at a low substrate concentration. The activities of S-oxidases were correlated with the contents of cytochrome P450 (CYP)3A enzymes. Anti-CYP3A2 antisera inhibited the activities of the S-oxidases catalyzing the reactions from FS to R-FSO (40%) and to S-FSO (60%) at the high substrate concentration and inhibited the activities of theS-oxidases, thus catalyzing reactions fromR-FSO and S-FSO to FSO2 (70%) at both high and low substrate concentrations. These results suggest that CYP3A is the major enzyme involved in all S-oxidation pathways in flosequinan metabolism in rats. On the other hand, except for the S-oxidation of FS to R-FSO, the rates of the other three S-oxidations by liver microsomes from 30 individual humans correlated highly with each other, suggesting that the same enzyme would be involved in the three S-oxidations. Anti-CYP3A2 antisera inhibited the activities of all theS-oxidases in human liver microsomes ranging from 40 to 80%, suggesting that CYP3A is also involved in all of theS-oxidations of flosequinan in humans. The American Society for Pharmacology and Experimental Therapeutics