Effects of 4-Cholestenone in Animals and in Man

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Abstract
Feeding 1% (body weight) [DELTA]4-cholestenone to rats in a synthetic diet arrested growth after 5 to 6 weeks. There was marked adrenocortical hypertrophy, up to 7 times control weights. Adrenal ascorbic acid and cholesterol concentrations were decreased by 80 to 90%. There was no thymic involution. Direct measurements of corticosterone output in adrenal vein blood revealed values only 15% of those in control pair fed animals. Normal growth was not restored by administration of cortisone or of corticosterone but adrenal hypertrophy was prevented. Simultaneous feeding of cholesterol with cholestenone afforded partial protection against toxic effects of the latter. Growth inhibition and adrenal hypertrophy were less marked. Absorption of cholestenone-4-C14 was not decreased by simultaneous cholesterol feeding. There was over 70% complete absorption of a 9.4 mg dose of cholestenone-4-C14. Over 90% of the radioactivity in the carcass was digitonin precipitable, presumably dihydrocholesterol. Dihydrocholesterol accumulated in liver and serum and in the adrenal gland. Serum cholesterol levels were decreased up to 50% but total serum sterol was not lowered. Dihydrocholesterol fed at a level of 1% did not impair growth but did cause a two-fold increase in adrenal weight. [DELTA]4-cholestenone strongly inhibited cholesterol synthesis. Fed to hyper-cholesterolemic patients (2.5 to 5 g per day) cholestenone did not decrease serum cholesterol levels and led to extremely high concentrations of dihydrocholesterol (200 to 500 mg%).