Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia.
Ortho,para,dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane (Roussell)) is used as an adrenolytic drug to reduce adrenocortical mass and circulating cortisol levels in Cushing's syndrome but has the unwanted side-effect of inducing hypercholesterolaemia. This paper examined the mechanism of that effect in 30 patients with Cushing's syndrome treated with o,p'DDD during the past 10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly by increasing LDL-cholesterol. The latter effect was not due to impaired binding of LDL to its receptor, as shown in vitro using cultured fibroblasts. Increases in plasma mevalonic acid during o,p'DDD administration were suggestive of increased cholesterol synthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemia by increasing cholesterol synthesis. It is proposed that this effect is due to the drug's known ability to block cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for down-regulating hepatic cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reverses the hyperlipidaemia and enables o,p'DDD therapy to be maintained without increasing cardiovascular risk.
Maher
V M
VM
MRC Lipoprotein Team, Hammersmith Hospital, London, UK.
Trainer
P J
PJ
Scoppola
A
A
Anderson
J V
JV
Thompson
G R
GR
Besser
G M
GM
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D002784:Cholesterol / Q000096:biosynthesis; D003480:Cushing Syndrome / Q000188:drug therapy / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy; D008055:Lipids / Q000097:blood; D008148:Lovastatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D008798:Mevalonic Acid / Q000097:blood; D008875:Middle Aged; D008939:Mitotane / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D019821:Simvastatin
D000924:Anticholesteremic Agents; D008055:Lipids; D008939:Mitotane; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D008798:Mevalonic Acid