Expression cloning of an oxysterol 7 alpha-hydroxylase selective for 24-hydroxycholesterol

The synthesis of 7 alpha-hydroxylated bile acids from oxysterols requires a n oxysterol 7 alpha-hydroxylase encoded by the Cyp7b1 locus. As expected, m ice deficient in this enzyme have elevated plasma and tissue levels of 25- and 27-hydroxycholesterol; however, levels of another major oxysterol, 24-h ydroxycholesterol, are not increased in these mice, suggesting the presence of another oxysterol 7 alpha-hydroxylase. Here, we describe the cloning an d char acterization of murine and human cDNAs and genes that encode a secon d oxysterol 7 alpha-hydroxylase. The genes contain 12 exons and are located on chromosome 6 in the human (CYP39A1 locus) and in a syntenic position on chromosome 17 in the mouse (Cyp39a1 locus). CYP39A1 is a microsomal cytoch rome P450 enzyme that has preference for 24-hydroxycholesterol and is expre ssed in the liver. The levels of hepatic CYP39A1 mRNA do not change in resp onse to dietary cholesterol, bile acids, or a bile acid-binding resin, unli ke those encoding other sterol 7 alpha-hydroxylases. Hepatic CYP39A1 expres sion is sexually dimorphic (female > male), which is opposite that of CYP7B 1 (male > female). We conclude that oxysterol 7 alpha-hydroxylases with dif ferent substrate specificities exist in mice and humans and that sexually d imorphic expression patterns of these enzymes in the mouse may underlie dif ferences in bile acid metabolism between the sexes.