Enzymatic formation and chemical synthesis of an active metabolite of 3β-hydroxy-5α-cholest-8(14)-en-15-one, a potent regulator of cholesterol metabolism

Abstract

The enzymatic (rat liver mitochondria) conversion of 3β-hydroxy-5α-cholest-8(14)-en-15-one to 5α-cholest-8(14)-ene-3β,26-diol-15-one is described. The enzymatic product was judged, on the basis of 1H and 13C NMR studies, to be a 4:1 mixture of its 25R and 25S isomers. (25R)-5α-Cholest-8(14)-ene-3β,26-diol-15-one was prepared through a five-step synthesis from (25R)-26-hydroxycholesterol. The (25R) isomer of the new compound was found to be highly active in the suppression of the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells and to inhibit the esterification of cholesterol in jejunal microsomes.