METABOLISM OF TERRITREM A IN LIVER MICROSOMES FROM MALE WISTAR RATS: 3. CYTOCHROME P-450 ISOFORMS CATALYZING TRA METABOLISM

Abstract

The cytochrome P-450 isoforms involved in territrem A (TRA) metabolism in liver microsomes of male Wistar rats have been characterized. Pretreatment with phenobarbital (PB) or dexamethasone (DEX) resulted in a similar significant increase in TRA metabolic activity. Although PB treatment resulted in a significant elevation in CYP2B, CYP2C11, and CYP3A levels, only CYP3A levels were significantly increased by DEX treatment. Cimetidine markedly reduced the formation of the TRA metabolites 4 g -hydroxymethyl-4 g -demethylterritrem A (MA 1 ), 4 g -oxo-4 g -demethylterritrem A (MAX) and 2-dihydro-4 g -demethylterritrem A (MA 2 ) in liver microsomes from 2-wk-old rats (mainly containing CYP3A2) and 7-wk-old rats (containing CYP2B, CYP2C11, and CYP3A2). SKF 525A, which inhibits CYP2B, CYP2C11, and CYP3A2, and orphenadrine, which inhibits CYP2B, also decreased MA 2 formation in liver microsomes from 7-wk-old phenobarbital-pretreated rats. The formation of MA 1 and MAX was not affected. Furthermore, an immunoinhibition study demonstrated that anti-CYP3A2 antibody reduced MA 1 , MAX, and MA 2 formation to nondetectable levels in liver microsomes from 2- and 7-wk-old rats, whereas anti-CYP2C11 or anti-CYP2B antibody, respectively, had no marked effect on MA 1 , MAX, and MA 2 formation in liver microsomes from 7-wk-old untreated or PB-treated rats. These results suggest that the CYP3A isoform is mainly responsible for MA 1 , MAX, and MA 2 formation in liver microsomes in male Wistar rats.