REGULATION OF THE LAST 2 ENZYMATIC-REACTIONS IN CHOLESTEROL-BIOSYNTHESIS IN RATS - EFFECTS OF BM-15.766, CHOLESTEROL, CHOLIC-ACID, LOVASTATIN, AND THEIR COMBINATIONS

The Smith-Lemli-Opitz syndrome is a common inherited birth disorder ca used by markedly reduced 7-dehydrocholesterol Delta(7)-reductase activ ity, the final enzyme in the cholesterol biosynthetic pathway, BM 15.7 66 [1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7 -dehydrocholesterol Delta(7)-reductase activity, reduces plasma choles terol levels, and increases 7-dehydrocholesterol levels to reproduce t he biochemical abnormalities of the syndrome in rats, Cholesterol, cho lic acid, and lovastatin, alone or in combinations, were fed to rats g iven BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5-dehydrogenase and 7-de hydrocholesterol Delta(7)-reductase, were measured, After feeding BM 1 5.766, hepatic 7-dehydrocholesterol Delta(7)-reductase activity decrea sed by 77% while lathosterol 5-dehydrogenase activity tended to increa se, so that the ratio of 5-dehydrogenase to Delta(7)-reductase activit ies increased from 0.33 to 2.8, In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and Delta(7)-reductase act ivities by 76% and 66%, respectively, and decreased the 5-dehydrogenas e: Delta(7)-reductase activities ratio from 2.8 to 2.2, In contrast, t reatment with cholic acid and BM 15.766 further inhibited Delta(7)-red uctase activity by 67% without changing significantly the 5-dehydrogen ase activity that had increased the ratio to 5.5, Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did no t change Delta(7)-reductase activity, raising the ratio to 14.3, In BM 15.766-treated rats, the first and last two enzymatic reactions in th e cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglut aryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol Delta(7)-reductase are down-regulated by choleste rol, Thus, only cholesterol and not cholic acid or lovastatin could re duce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766.