Susceptibility to cadmium (Cd) hepatotoxicity differs among inbred strains of mice. For example, C3H/HeJ mice are sensitive to Cd-induced hepatotoxicity, whereas DBA/2J mice are resistant. The mechanism of genetic predisposition to Cd hepatotoxicity is unknown. A contemporary theory for acute target organ intoxication maintains that Cd initially damages vascular endothelium and parenchymal cell injury is a secondary event that results from localized ischemia. In the present study, the hypothesis that hepatic endothelial cells (EC) of C3H mice are more susceptible to Cd toxicity than those of DBA mice was tested. Hepatic parenchymal and endothelial cells were grown separately on monolayer cultures for 22 h and subsequently treated with various concentrations of Cd. Hepatocellular toxicity was assessed by lactate dehydrogenase leakage and intracellular K+ loss, whereas endothelial cell injury was assessed by trypan blue exclusion and the inhibition of protein synthesis. The susceptibility of hepatocytes to the cytotoxic effects of Cd was identical between strains. In contrast, the vulnerability of EC to Cd intoxication was strain-dependent. When exposed to 2.5-10.0 microM Cd, EC of Cd-sensitive mice were more susceptible to the cytotoxic effects of Cd than those of Cd-resistant mice. Basal metallothionein (MT) levels as well as Cd uptake into EC were similar in the two strains. Following Cd exposure, EC of Cd-sensitive mice accumulated similar amounts of MT as EC of Cd-resistant mice. These observations suggest that the microvasculature in livers of inbred mice is the target tissue responsible for strain-dependent susceptibility to Cd-induced liver injury. The mechanisms that account for this genetic variation in endothelial cell response to Cd are unknown, but do not appear to be related to the cellular disposition of Cd nor to a defect in the metabolism of MT.