Changes in content of P450 isozymes in hepatic and renal microsomes of the male rat treated with cis-diamminedichloroplatinum

Abstract

1. The changes in the activity of drug-metabolizing enzymes and in the content of P450 isozymes in renal and hepatic microsomes after treatment of the male Sprague-Dawley rat with cis-diamminedichloroplatinum (Cisplatin, CDDP) were examined.

2. NADPH-P450 reductase activity in renal microsomes was significantly increased by treatment with CDDP, but lauric acid ω- and (ω-l)-hydroxylation activities of renal microsomes were not increased.

3. The level of P4502C23 was increased significantly and levels of P4504A2 and 4A8 tended to increase in renal microsomes.

4. In hepatic microsomes, lauric acid ω-hydroxylation activity was increased, but (ω-1)-hydroxylation activity was not. Levels of P4502C11 and 3A2, which are male-specific forms, were decreased, whereas levels of P4502A1, 2C7 and 2E1 were increased in hepatic microsomes. The levels of P4504A2 and 4A3 were increased by CDDP and the level of P4504A1 was not changed. Changes in the protein levels of P450 by CDDP were consistent with those in the mRNA levels reported previously (LeBlanc et al. 1992).

5. Male-specific forms in rat liver such as P4502C11 were decreased by CDDP, but those in the kidney such as P4504A2 was not. Therefore, CDDP has different influences on the regulation of hepatic and renal P450s.