REGULATION OF THE LAST 2 ENZYMATIC-REACTIONS IN CHOLESTEROL-BIOSYNTHESIS IN RATS - EFFECTS OF BM-15.766, CHOLESTEROL, CHOLIC-ACID, LOVASTATIN, AND THEIR COMBINATIONS
A. Honda et al., REGULATION OF THE LAST 2 ENZYMATIC-REACTIONS IN CHOLESTEROL-BIOSYNTHESIS IN RATS - EFFECTS OF BM-15.766, CHOLESTEROL, CHOLIC-ACID, LOVASTATIN, AND THEIR COMBINATIONS, Hepatology, 24(2), 1996, pp. 435-439
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.