Dexamethasone induction of taxol metabolism in the rat

This study examined the effect of dexamethasone (DEX), 100 mg/kg/day for 3 days, on [3H]taxol metabolism in liver microsomes and hepatocytes of male and female Sprague-Dawley rats. In control rats, two isomeric monohydroxylated metabolites, M1 and M2, were formed. The formation of both metabolites was 2-3 times greater in the male than in the female animals. After DEX treatment, M1 increased 2.6-fold in the male animals and 6.5-fold in the female animals. This was accompanied by similar increases in hepatic cytochrome P4503A protein and testosterone 6 beta-hydroxylation. Three additional metabolites (U1, U2, and U3) were formed in the DEX-treated animals only. Isolation of these metabolites from rat hepatocyte incubates by reversed-phase HPLC permitted structure identification of U2 and U3, using tandem MS. The mass spectrum of U3 was consistent with deacetylation of taxol, whereas the mass spectrum of U2 was consistent with deacetylation of the monohydroxylated taxol metabolite M2. A comparison of HPLC and MS data for U3 with those of standard 10-deacetyltaxol suggested that the site of deacetylation might be the 4-position of the taxane ring. Preliminary observations indicate that the deacetylation is caused by a DEX-inducible cytochrome P450.