Regulation of the last two 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 caused by markedly reduced 7-dehydrocholesterol delta 7-reductase activity, the final enzyme in the cholesterol biosynthetic pathway. BM 15.766 (4-[2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7-dehydrocholesterol delta 7-reductase activity, reduces plasma cholesterol levels, and increases 7-dehydrocholesterol levels to reproduce the biochemical abnormalities of the syndrome in rats. Cholesterol, cholic acid, and lovastatin, alone or in combinations, were fed to rats given BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5-dehydrogenase and 7-dehydrocholesterol delta 7-reductase, were measured. After feeding BM 15.766, hepatic 7-dehydrocholesterol delta 7-reductase activity decreased by 77% while lathosterol 5-dehydrogenase activity tended to increase, so that the ratio of 5-dehydrogenase to delta 7-reductase activities increased from 0.33 to 2.8. In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and delta 7-reductase activities by 76% and 66%, respectively, and decreased the 5-dehydrogenase: delta 7-reductase activities ratio from 2.8 to 2.2. In contrast, treatment with cholic acid and BM 15.766 further inhibited delta 7-reductase activity by 67% without changing significantly the 5-dehydrogenase activity that had increased the ratio to 5.5. Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did not 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 the cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol delta 7-reductase are down-regulated by cholesterol. Thus, only cholesterol and not cholic acid or lovastatin could reduce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766.
Honda
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Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, USA.
Shefer
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Salen
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Xu
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Batta
A K
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Tint
G S
GS
Honda
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Chen
T C
TC
Holick
M F
MF
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000494:pharmacology; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000924:Anticholesteremic Agents; D002793:Cholic Acids; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010879:Piperazines; C047457:BM 15766; D002784:Cholesterol; D008148:Lovastatin; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D019826:Cholic Acid