CYCLOPHOSPHAMIDE MODULATES RAT HEPATIC CYTOCHROME-P450 2C11 AND STEROID 5-ALPHA-REDUCTASE ACTIVITY AND MESSENGER-RNA LEVELS THROUGH THE COMBINED ACTION OF ACROLEIN AND PHOSPHORAMIDE MUSTARD

Cyclophosphamide treatment of adult male rats leads to sustained decre ases in several liver microsomal cytochrome P450 (CYP) activities, inc luding CYP 2C11-catalyzed cyclophosphamide activation, via a process t hat is associated with a feminization of the overall pattern of liver enzyme expression (G. A. LeBlanc and D. J. Waxman, Cancer Res., 50: 57 20-5726, 1990). The present study compares the effects of cyclophospha mide and its isomeric analogue ifosphamide on the gender-dependent exp ression of hepatic CYP 2C11 and steroid 5alpha-reductase in adult male rats and also examines the role of the cyclophosphamide metabolites a crolein and phosphoramide mustard in feminizing the expression of thes e liver enzymes. Ifosphamide (a) suppressed the male-specific CYP 2C11 mRNA and CYP 2C11-catalyzed liver microsomal testosterone 2alpha-hydr oxylation and cyclophosphamide and ifosphamide 4-hydroxylation and (b) elevated the female-dominant liver enzyme steroid 5alpha-reductase an d its mRNA 7-9 days after drug treatment, both occurring in a manner s imilar to that of cyclophosphamide, but requiring a 50% higher dose (1 80 mg/kg, single i.p. injection) to achieve these effects. This patter n of response could not be achieved by treatment of rats with acrolein or with cyclophosphamide analogues that decompose to acrolein without formation of phosphoramide mustard. In contrast, phosphoramide mustar d treatment (100 mg/kg) did modulate microsomal CYP 2C11 and steroid 5 alpha-reductase activities. Treatment with a lower dose (50 mg/kg) of phosphoramide mustard or with the acrolein precursor 4-hydroperoxydech lorocyclophosphamide (200 mg/kg) alone did not affect liver enzyme exp ression, whereas the combination of these agents produced an overall p attern of response that was similar to that conferred by cyclophospham ide. These studies establish that ifosphamide is less potent than cycl ophosphamide in modulating the pattern of cytochrome P450 and steroid 5alpha-reductase expression and that phosphoramide mustard is responsi ble for the modulation of liver enzyme expression by cyclophosphamide, with acrolein potentiating the modulating activity of the mustard.