Abstract
To investigate the mechanism by which o,p′-DDD (2,2-bis[2-chlorophenyl-4-chloro-phenyl]-1,1-dichloroethane; Mitotane) produces hypercholesterolemia in man, we studied the effect of the drug on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in reverse light-cycled rats. o,p′-DDD markedly stimulated reductase activity in vivo and in vitro in a dose-dependent manner. This effect was not associated with demonstrable adrenocortical toxicity or changes in plasma corticosterone concentrations. Thus, o,p′-DDD may elevate circulating cholesterol levels in man by increasing endogenous cholesterol synthesis. In addition, the o,p′-DDD-treated rat may serve as a useful model for testing other agents for the ability to suppress endogenous cholesterol synthesis and lower circulating cholesterol levels.
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