LIPIDS AND LIPOPROTEINS
Expression Cloning of an Oxysterol 7α-Hydroxylase Selective for 24-Hydroxycholesterol*

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The synthesis of 7α-hydroxylated bile acids from oxysterols requires an oxysterol 7α-hydroxylase encoded by theCyp7b1 locus. As expected, mice deficient in this enzyme have elevated plasma and tissue levels of 25- and 27-hydroxycholesterol; however, levels of another major oxysterol, 24-hydroxycholesterol, are not increased in these mice, suggesting the presence of another oxysterol 7α-hydroxylase. Here, we describe the cloning and characterization of murine and human cDNAs and genes that encode a second oxysterol 7α-hydroxylase. The genes contain 12 exons and are located on chromosome 6 in the human (CYP39A1locus) and in a syntenic position on chromosome 17 in the mouse (Cyp39a1 locus). CYP39A1 is a microsomal cytochrome P450 enzyme that has preference for 24-hydroxycholesterol and is expressed in the liver. The levels of hepatic CYP39A1 mRNA do not change in response to dietary cholesterol, bile acids, or a bile acid-binding resin, unlike those encoding other sterol 7α-hydroxylases. Hepatic CYP39A1 expression is sexually dimorphic (female > male), which is opposite that of CYP7B1 (male > female). We conclude that oxysterol 7α-hydroxylases with different substrate specificities exist in mice and humans and that sexually dimorphic expression patterns of these enzymes in the mouse may underlie differences in bile acid metabolism between the sexes.

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Published, JBC Papers in Press, March 27, 2000, DOI 10.1074/jbc.M001810200

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This work was supported by National Institutes of Health Grant HL 20948, Robert A. Welch Foundation Grant I-0971, and the William M. Keck Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AF237981 and AF237982.