Lack of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase in fibroblasts from a child with urinary excretion of 3 beta-hydroxy-delta 5-bile acids. A new inborn error of metabolism.
Cultured fibroblasts were shown to be capable of catalyzing the conversion of 7 alpha-hydroxy-cholesterol to 7 alpha-hydroxy-4-cholesten-3-one, an important reaction in bile acid synthesis. The apparent Km was approximately 7 mumol/liter and Vmax varied between 3 and 9 nmol/mg protein per h under the assay conditions used. The assay was used to investigate fibroblasts from a patient who presented with a familial giant cell hepatitis and who was found to excrete the monosulfates of 3 beta, 7 alpha-dihydroxy-5-cholenoic acid and 3 beta, 7 alpha, 12 alpha-trihydroxy-5-cholenoic acid in urine (Clayton, P. T., J. V. Leonard, A. M. Lawson, K. D. R. Setchell, S. Andersson, B. Egestad, and J. Sjövall. 1987. J. Clin. Invest. 79:1031-1038). In addition 7 alpha-hydroxy-cholesterol was found to accumulate in the circulation. Cultured fibroblasts from this boy were completely devoid of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase activity. Fibroblasts from his parents had reduced activity, compatible with a heterozygous genotype. The results provide strong evidence for the suggestion that this patient's liver disease was caused by a primary defect in the 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase involved in bile acid biosynthesis.
Buchmann
M S
MS
Institute of Clinical Biochemistry, Rikshospitalet, University of Oslo, Norway.
Kvittingen
E A
EA
Nazer
H
H
Gunasekaran
T
T
Clayton
P T
PT
Sjövall
J
J
Björkhem
I
I
D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000652:urine*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007700:Kinetics; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology*; D008297:Male; D010375:Pedigree; D013379:Substrate Specificity; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D001647:Bile Acids and Salts; D015096:3-Hydroxysteroid Dehydrogenases; D005723:gamma-Glutamyltransferase