The inhibitory effect of cadmium (7440439), zinc (7440666) and lead (7439921) were investigated in-vitro on microsomal preparations of guinea-pig livers, kidneys, and lungs. Microsomes were obtained from hepatic, renal and pulmonary tissues of male English-Short-Hair- guinea-pigs by differential centrifugation. Microsomal preparations were preincubated and metals were added to the preincubation medium as chloride salts. After preincubation, samples were assayed for enzyme activity. Control flasks contained either preincubated microsomes without metals, or preincubated microsomes to which metals were added. After preincubation, benzo(a)pyrene hydroxylase and benzphetamine demethylase activities were assayed. The metals were used at 200 micromolar concentrations. Preincubation of liver, adrenal and pulmonary microsomes with cadmium for 60 minutes decreased benzphetamine demethylase and benzo(a)pyrene hydroxylase activities in all three tissues. Small amounts of cadmium added to the microsomal suspensions after the preincubation period did not have any effect on enzyme activity. Preincubation of hepatic, adrenal or pulmonary microsomes with zinc had the same effect as cadmium. Lead did not have any preincubated effect on metabolism. Zinc and cadmium decreased monooxygenase activities only after preincubation with microsomal suspension. The extent of inhibition of these enzymes by cadmium and zinc was dependent on concentration of the metals present during the preincubation period. It was also dependent upon the duration of the incubation period. Cadmium inhibited adrenal and pulmonary monooxygenases to a greater degree than hepatic enzymes at all concentrations. A similar effect was seen with zinc. The decline in enzyme activity produced by both metals was temperature dependent during the preincubation period in all three tissues. The authors conclude that the inhibitory effects of cadmium and zinc in-vitro on microsomal monooxygenases in liver, lung, and adrenal are dependent on duration of prior exposure of microsomal preparations to the metals.