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J. Biol. Chem., Vol. 275, Issue 22, 16543-16549, June 2, 2000
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From the Department of Molecular Genetics, University of Texas
Southwestern Medical Center, Dallas, Texas 75235-9046
The synthesis of 7 The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF237981 and AF237982.
Expression Cloning of an Oxysterol 7
-Hydroxylase Selective for
24-Hydroxycholesterol*
-hydroxylated bile acids
from oxysterols requires an oxysterol 7-hydroxylase encoded by the
Cyp7b1 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 7-hydroxylase. Here, we describe the
cloning and characterization of murine and human cDNAs and genes
that encode a second oxysterol 7-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 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 7-hydroxylases. Hepatic
CYP39A1 expression is sexually dimorphic (female > male), which
is opposite that of CYP7B1 (male > female). We conclude that
oxysterol 7-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.
*
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.
To whom correspondence should be addressed: Dept. of Molecular
Genetics, University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd., Dallas, TX 75235-9046. Tel.: 214-648-2007; Fax:
214-648-6899; E-mail: Russell@utsw.swmed.edu.
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