Abstract
The accumulation of various 25-hydroxylated C(27)-bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27) gene. These bile alcohols may be intermediates in the alternative cholic acid side chain cleavage pathway. The present study was undertaken to identify enzymes and reactions responsible for the formation of these bile alcohols and to explain why Cyp27(-/-) mice do not show CTX-related abnormalities. Microsomal activities of 5beta-cholestane-3alpha,7alpha,12alpha-triol 25- and 26-hydroxylases, 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol 23R-, 24S-, and 27-hydroxylases and testosterone 6beta-hydroxylase, a marker enzyme for CYP3A, in Cyp27(-/-) mice livers were markedly up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold, respectively). In contrast, these enzyme activities were not increased in CTX. The activities of 5beta-cholestane-3alpha,7alpha,12alpha-triol 25- and 26-hydroxylases and 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol 23R-, 24R-, 24S-, and 27-hydroxylases were strongly correlated with the activities of testosterone 6beta-hydroxylase in control human liver microsomes from eight unrelated donors. Troleandomycin, a specific inhibitor of CYP3A, markedly suppressed these microsomal side chain hydroxylations in both mouse and human livers in a dose-dependent manner. In addition, experiments using recombinant overexpressed human CYP3A4 confirmed that these microsomal side chain hydroxylations were catalyzed by a single enzyme, CYP3A4. The results demonstrate that microsomal 25- and 26-hydroxylations of 5beta-cholestane-3alpha,7alpha,12alpha-triol and microsomal 23R-, 24R-, 24S-, and 27-hydroxylations of 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol are mainly catalyzed by CYP3A in both mice and humans. Unlike Cyp27(-/-) mice, CYP3A activity was not up-regulated despite marked accumulation of 5beta-cholestane-3alpha,7alpha,12alpha-triol in CTX.
Highlights
From the ‡Department of Gastroenterology, University of Tsukuba, Tsukuba-city 305-8575, Japan, the §Gastrointestinal Division, Department of Medicine, and Liver Center, the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, the ¶Veterans Affairs Medical Center, East Orange, New Jersey 07018, the **Department of Medicine, Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah University Hospital, 91120 Jerusalem, Israel, and the ‡‡Department of Medicine, University of California and Veterans Affairs Medical Center, San Francisco, California 94121
The accumulation of various 25-hydroxylated C27-bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27) gene
The present study was undertaken to identify the enzymes responsible for the formation of bile alcohols other than 5cholestane-3␣,7␣,12␣,25-tetrol, and to explain why Cyp27Ϫ/Ϫ mice accumulate less amounts of bile acid intermediates compared with CTX
Summary
Vol 276, No 37, Issue of September 14, pp. 34579 –34585, 2001 Printed in U.S.A. Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27؊/؊ Mice but Not in Cerebrotendinous Xanthomatosis*. The accumulation of various 25-hydroxylated C27-bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27) gene. These bile alcohols may be intermediates in the alternative cholic acid side chain cleavage pathway. Microsomal activities of 5-cholestane-3␣,7␣,12␣-triol 25- and 26-hydroxylases, 5-cholestane-3␣,7␣,12␣,25-tetrol 23R-, 24S-, and 27-hydroxylases and testosterone 6-hydroxylase, a marker enzyme for CYP3A, in Cyp27؊/؊ mice livers were markedly up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold, respectively). The results showed that CYP3A catalyzed 25-hydroxylation of 5-cholestane-3␣,7␣,12␣-triol and car-
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