Studies on the mechanism of cadmium-induced inhibition of the hepatic microsomal monooxygenase of the male rat

Abstract

Cadmium is a potent inhibitor of hepatic drug metabolism but little is known about the biochemical mechanisms involved. Male rats receiving a single dose of cadmium acetate (2.0 mg Cd 2+/kg, ip) exhibited significant decreases in hepatic microsomal metabolism of hexobarbital (79%), ethylmorphine (71%), and aniline (47%), as well as decreased amounts of both microsomal cytochrome P-450 (39%) and cytochrome b 5 (30%) 72 hr after administration of the metal. In addition, the magnitudes of microsomal hexobarbital, ethylmorphine, and aniline binding spectra were significantly reduced. NADPH-cytochrome c reductase activity was not altered. In vitro addition of Cd 2+ (10 −6 to 10 −3 m) to liver microsomes produced a concentration-dependent inhibition of the metabolism of the substrates tested, a reduction in the level of cytochrome P-450 which was accompanied by an increase in the level of the inactive form of the hemo-protein, P-420, and decreases in the microsomal binding spectra of the three substrates. In kinetic studies, apparent V max values were significantly lowered for ethylmorphine N-demethylase (75%) and aniline hydroxylase (57%) by cadmium treatment. The apparent K m value for aniline hydroxylase was not altered, but that for ethylmorphine N-demethylase was significantly decreased following cadmium treatment. After in vitro cadmium addition, concentration-dependent decreases were observed in the apparent V max and K m values for both microsomal reactions.