MECHANISMS OF CYCLOPHOSPHAMIDE ACTION ON HEPATIC P-450 EXPRESSION

  • 15 September 1990
    • journal article
    • research article
    • Vol. 50  (18) , 5720-5726
Abstract
Cyclophosphamide was administered to adult male rats (130 mg/kg, single i.p. injection) and its effects on the P-450 enzymes that contribute to the activation of this drug in rat liver were then assessed. P-450-mediated cyclophosphamide 4-hydroxylase activity in isolated rat liver microsomes decreased by approximately 70% over a 9-day period following drug treatment. This decrease was due to the loss of cytochrome P-450 form 2c (IIC11), a major contributor to cyclophosphamide 4-hydroxylation in untreated male rat liver, while the other major hepatic cyclophosphamide 4-hydroxylase. P-450 PB-1 (IIC6), was largely unaffected. The loss of P-450 2c activity did not result from a decrease in P-450 reductase or from direct inactivation of the P-450 protein by cyclophosphamide or its metabolites, but rather was due to a reduction in hepatic P-450 2c protein and mRNA levels. Hepatic P-450 2a (IIIa2)and P-450 RLM2(IIA2) were also suppressed by cyclophosphamide treatment. Serum testosterone, which contributes to the expression of P-450s 2c, 2a and RLM2, was severely depleted in the cyclophosphamide-treated rats; however, this loss was not the direct cause of the decreases in these hepatic P-450s, since the decreases were not reversed upon restoration of normal testosterone levels by human chorionic gondotropin stimulation of testicular androgen production. In contrast to the suppression of these testoterone-dependent P-450s, P-450 3 (IIA1), P-450j (IIE1), and the P-450-independent microsomal enzyme steroid 5.alpha.-reductase were each elevated in rat liver following cyclophosphamide administration. In contrast to P-450 3 and steroid 5.alpha.-reductase, however, the elevation of P-450j protein was transient and was not accompanied by an increase in P-450j-associated hepatic microsomal aniline hydroxylase activity. In vitro experiments revealed that P-450j was severalfold more susceptible to inactivation by the cyclophosphamide metabolite acrolein as compared with P-450 3. These observations suggest that P-450j protein is induced by cyclophsophamide treatment but that the protein is inactivated by the cyclophosphamide metabolite acrolein. These findings establish that cyclophosphamide treatment can modulate hepatic P-450 activities through multiple mechanisms and in a manner that may alter P-450 metabolism of cyclophsophamide and perhaps other anticancer drugs that undergo bioactivation in the liver.

This publication has 21 references indexed in Scilit: