Tolerance development to cadmium-induced decrease in hepatic oxidative xenobiotic metabolism and cytochrome P-450 content in the male rat.

Abstract

Cadmium, in dose of 0.84 mg/kg (ip), produces a marked inhibition in hepatic oxidative xenobiotic metabolism which results from a decreased cytochrome P-450 content in the male rat. The inhibitions in microsomal metabolism of aniline, ethylmorphine, or p-nitroanisole were not elicited by the 0.84 mg/kg cadmium dose in rats which had been pretreated (72 hours prior) with a lower dose of cadmium (0.21 mg Cd/kg, ip). Likewise, the decreases in both microsomal cytochrome P-450 content and in microsomal spectral binding of hexobarbital or aniline produced by the 0.84 mg/kg cadmium dose were not elicited in the rats pretreated with the low cadmium dose. The 0.21 mg/kg cadmium dose produced an increase (370%) in the cadmium-binding capacity as well as an increase (395%) in total hepatic metallothionein. These data are consistent with the hypothesis that the pretreatment of animals with relatively low cadmium doses produces an increase in the cellular levels of metallothionein which can then bind and ameliorate the toxicological effects of a subsequently administered toxic dose of cadmium.