| Abstract: | Ortho, para, dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane(Roussell)) is used as an adrenolytic drug to reduce adrenocorticalmass and circulating cortisol levels in Cushing's syndrome buthas the unwanted side-effect of inducing hypercholesterolaemia.This paper examined the mechanism of that effect in 30 patientswith Cushing's syndrome treated with o,p'DDD during the past10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly byincreasing LDL-cholesterol. The latter effect was not due toimpaired binding of LDL to its receptor, as shown in vitro usingcultured fibroblasts. Increases in plasma mevalonic acid duringo,p'DDD administration were suggestive of increased cholesterolsynthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemiaby increasing cholesterol synthesis. It is proposed that thiseffect is due to the drug's known ability to block cytochromeP450-mediated reactions, thus impairing the formation of oxysterolsresponsible for down-regulating hepatic cholesterol synthesis.Treatment with simvastatin, an inhibitor of cholesterol synthesis,reverses the hyperlipidaemia and enables o,p'DDD therapy tobe maintained without increasing cardiovascular risk. |
