With the continuing concern over both steroid compounds and metals as potential environmental pollutants, the interactions between these compounds could become an important health issue. In our continuing study of the interactions of cadmium with various steroids we recently found that testosterone pretreatment protects against cadmium-induced toxicity in C57 mice but has no effect in C3H mice. The basis of this strain-specific acquired tolerance to cadmium is still unclear. In this study, we examined the effects of the antiandrogen cyproterone acetate (CA) on the toxicokinetics and toxicity of cadmium and on the ability of cadmium to induce metallothionein (MT) in male C57 and C3H mice. To assess the tissue accumulation of cadmium, the mice were given CA (10 mg/kg, sc, at 48, 24, and 0 h) prior to cadmium (10 mumol/kg, 0 h). The tissue distribution of cadmium was markedly affected by CA pretreatment, as accumulation of cadmium in liver of both strains was reduced 24 h after cadmium administration. Renal cadmium levels were not affected in either strain by CA. CA pretreatment reduced testicular accumulation of cadmium in C57 mice but not in C3H mice. Cadmium alone, CA alone, or CA and cadmium in combination were not toxic at the doses studied as reflected by the absence of changes in serum glutamic-oxaloacetic transaminase (GOT) activity, lactate dehydrogenase (LDH) activity, and blood urea nitrogen (BUN). CA alone increased MT synthesis in the liver of both strains of mice. However, the cadmium-induced MT level in the livers of both strains of mice was markedly decreased by CA pretreatment. In the C57 mice cadmium-induced renal MT levels were also substantially reduced by CA pretreatment but not in the C3H mice. In addition, the levels of cadmium-binding protein within testes were not affected by CA with or without additional cadmium treatment. These results indicate that, despite the fact that CA will itself induce MT in the liver, pretreatment with CA reduces cadmium induction of hepatic and, in some cases, renal MT synthesis. This reduction may be secondary to a reduced accumulation of cadmium in the liver, but this does not hold true for the kidney.