Cadmium administered in vivo was an effective inhibitor of hepatic σ-aminolevulinic acid (ALA) synthetase and an effective stimulator of hepatic heme oxygenase in male mice. Cadmium inhibited the 3, 5-dicarboethoxy-1, 4-dihydrocollidine (DDC)-mediated induction of ALA synthetase when administered 1 hr prior to, or 1 hr subsequent to, the administration of DDC. Cadmium also inhibited the DDC-mediated induction of ALA synthetase when administered 3 hr following the administration of DDC. However, the degree of inhibition was lower than that obtained by administering cadmium 1 hr before or after administration of DDC. Hemin, a well known feed-back repressor of ALA synthetase, was also administered to mice for comparison with the effect of cadmium on the enzyme. Hemin inhibited the DDC-mediated induction of ALA synthetase much more effectively than cadmium when administered 3 hr following the administration of DDC. The administration of cadmium to mice significantly increased hepatic heme oxygenase activity. Pretreatment of mice with cycloheximide almost completely blocked the cadmium-mediated initial increase of heme oxygenase activity, but pretreatment with actinomycin D was less effective, suggesting that cadmium acts at a post-transcriptional step in the synthesis of the enzyme. It is shown that pretreatment of animals with cadmium reduces the toxicity against the subsequent higher dose of the metal. Such protective effect was also observed in the present investigation ; namely, pretreatment of mice with cadmium itself reduced the inhibitory effect on the DDC-mediated induction of ALA synthetase and partially inhibited the initial increase of heme oxygenase activity due to the subsequent administration of the metal. These data suggest that the decrease in cytochrome levels and the inhibition of drugmetabolizing enzyme activity seen following the administration of cadmium to rats or mice are the results of inhibition of ALA synthetase and stimulation of heme oxygenase leading to a decrease in heme levels required for the synthesis of cytochrome P-450.