STUDIES ON THE MECHANISM OF CADMIUM-INDUCED INHIBITION OF THE HEPATIC MICROSOMAL MONO-OXYGENASE OF THE MALE-RAT

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 Cd2+/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 b5 (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 Cd2+ (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 Vmax values were significantly lowered for ethylmorphine N-demethylase (75%) and aniline hydroxylase (57%) by cadmium treatment. The apparent Km 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 Vmax and Km values for both microsomal reactions. © 1979.