DEXAMETHASONE INDUCTION OF TAXOL METABOLISM IN THE RAT

This study examined the effect of dexamethasone (DEX), 100 mg/kg/day f or 3 days, on [H-3]taxol metabolism in liver microsomes and hepatocyte s of male and female Sprague-Dawley rats, In control rats, two isomeri c monohydroxylated metabolites, M(1) and M(2), were formed. The format ion of both metabolites was 23 times greater in the male than in the f emale animals. After DEX treatment, M(1) increased 2.6-fold in the mal e animals and 6.5-fold in the female animals. This was accompanied by similar increases in hepatic cytochrome P4503A protein and testosteron e 6 beta-hydroxylation. Three additional metabolites (U-1, U-2, and U- 3) were formed in the DEX-treated animals only. Isolation of these met abolites from rat hepatocyte incubates by reversed-phase HPLC permitte d structure identification of U-2 and U-3, using tandem MS. The mass s pectrum of U-3 was consistent with deacetylation of taxol, whereas the mass spectrum of U-2 was consistent with deacetylation of the monohyd roxylated taxol metabolite M(2). A comparison of HPLC and MS data for U-3 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-induc ible cytochrome P450.