RT Journal Article
SR Electronic
T1 The Nuclear Receptors Constitutive Active/Androstane Receptor and Pregnane X Receptor Activate the <em>Cyp2c55</em> Gene in Mouse Liver
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1177
OP 1182
DO 10.1124/dmd.110.032334
VO 38
IS 7
A1 Konno, Yoshihiro
A1 Kamino, Hiroki
A1 Moore, Rick
A1 Lih, Fred
A1 Tomer, Kenneth B.
A1 Zeldin, Darryl C.
A1 Goldstein, Joyce A.
A1 Negishi, Masahiko
YR 2010
UL http://dmd.aspetjournals.org/content/38/7/1177.abstract
AB Mouse CYP2C55 has been characterized as an enzyme that catalyzes synthesis of 19-hydroxyeicosatetraenoic acid (19-HETE), an arachidonic acid metabolite known to have important physiological functions such as regulation of renal vascular tone and ion transport. We have now found that CYP2C55 is induced by phenobarbital (PB) and pregnenolone 16α-carbonitrile (PCN) in both mouse kidney and liver. The nuclear xenobiotic receptors constitutive active/androstane receptor (CAR) and pregnane X receptor (PXR) regulate these drug inductions: CYP2C55 mRNA was increased 25-fold in PB-treated Car(+/+) but not in Car(−/−) mice and was induced in Pxr(+/+) but not Pxr(−/−) mice after PCN treatment. Cell-based promoter analysis and gel shift assays identified the DNA sequence −1679TGAACCCAGTTGAACT−1664 as a DR4 motif that regulates CAR- and PXR-mediated transcription of the Cyp2c55 gene. Chronic PB treatment increased hepatic microsomal CYP2C55 protein and serum 19-HETE levels. These findings indicate that CAR and PXR may play a role in regulation of drug-induced synthesis of 19-HETE in the mouse. U.S. Government work not protected by U.S. copyright