M Kitada — Page 15 | Search PubMed

PubMedDate not supplied

Rat liver microsomal cytochrome P-450 responsible for reductive metabolism of zonisamide.

The reductive metabolism of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide) to 2-sulfamoylacetylphenol (SMAP) was observed in liver microsomes from female rats, as well as male rats, but the SMAP-producing activity in female rats was 4-fold lower than that found in male rats. In addition, the reductive metabolism of zonisamide in liver microsomes was induced by the treatment of male rats with phenobarbital. However, the SMAP-producing activity did not correlate positively with the amounts of P-450 2B1 and P-450 2C11 immunochemically determined. In contrast, the reductive metabolism of zonisamide was also found to be induced by the pretreatment of male rats with pregnenolone 16 alpha-carbonitrile, triacetyloleandomycin, and dexamethasone. Furthermore, the SMAP-producing activity correlated highly with the amount of P-450 cross-reactive with antihuman P-450 3A4 antibody, suggesting that P-450 3A1/2 may function in the reductive metabolism of zonisamide. In addition, the P-450 PCNa (3A2) exhibited the SMAP-producing activity in a reconstituted system. The antihuman P-450 3A4 antibody inhibited markedly the formation of SMAP from zonisamide in male rat liver microsomes. These results indicate that cytochrome(s) P-450 belonging to P-450 3A subfamily may be predominantly responsible for the reductive metabolism of zonisamide in rat liver microsomes.

Anaerobiosis↗

PubMedDate not supplied

Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats.

Clarithromycin and its metabolites have been examined for their abilities to induce specific form(s) of cytochrome P-450 and metabolite complex formation in rats. Pretreatment of rats with clarithromycin,N-demethyl clarithromycin, clarithromycin N-oxide, and decladinosyl clarithromycin resulted in 48-75% decreases in the amount of 2C11 and 100-600% increases in the amount of 3A1. Clarithromycin and N-demethyl clarithromycin, but not decladinosyl clarithromycin, produced a metabolite complex with cytochrome P-450 in vivo. Activities of testosterone 2 beta- and 6 beta-hydroxylases were increased by administration of clarithromycin and N-demethyl clarithromycin when these activities were measured in the presence of ferricyanide, but not significant induction was observed when measured in the absence of ferricyanide. Clarithromycin N-oxide treatment resulted in the increase in hydroxylation of testosterone not only at the 2 beta- and 6 beta-positions (430 and 190%, respectively), but also at 7 alpha-position (60%), regardless of the presence or absence of ferricyanide. In vitro experiments with hepatic microsomes of dexamethasone-pretreated rats indicated that the metabolites that were modified at the tertiary amino group more efficiently produced the metabolite complex with cytochrome P-450 compared with the parent compound. In contrast, decladinosyl and hydroxylated metabolites had similar or lower capacities for metabolite complex formation than did the parent compound. Clarithromycin and its N-modified metabolites were able to induce 3A1 and form a metabolite complex with cytochrome P-450 in vivo in varying extents. Decladinosyl clarithromycin has a weak inducibility of 3A1 and did not form a metabolite complex with cytochrome P-450 in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗