Markedly Inhibited 7-Dehydrocholesterol-A7-Reductase Activity in Liver

We investigated the enzyme defect in late cholesterol biosyn-thesis in the Smith-Lemli-Opitz syndrome, a recessively in-herited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ con-genital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are bio-chemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the trans-formation of the precursors, [3a-3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver micro-somes from seven controls and four Smith-Lemli-Opitz ho-mozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120+8 vs 100+7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydro-cholesterol to yield cholesterol catalyzed by 7-dehydro-cholesterol-A7-reductase was nine times greater in controls than homozygotes microsomes (365±23 vs 40+4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydroge-nase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydro-cholesterol-A7-reductase is inherited abnormally in Smith