Abstract
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.
Footnotes
This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grants Z01-ES7100501, Z01-ES025034, Z01-ES050167, Z01-ES02124] (to M.N., D.C.Z., K.B.T., and J.A.G., respectively).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.032334.
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ABBREVIATIONS:
- P450
- cytochrome P450
- AA
- arachidonic acid
- CAR
- constitutive active/androstane receptor
- PXR
- pregnane X receptor
- PCN
- pregnenolone 16α-carbonitrile
- HETE
- hydroxyeicosatetraenoic acid
- EET
- epoxyeicosatrienoic acid
- PB
- phenobarbital
- DMSO
- dimethyl sulfoxide
- DEN
- diethylnitrosamine
- C3H
- C3H/HeNCrlBR (mice)
- NIEHS
- National Institute of Environmental Health Sciences
- PCR
- polymerase chain reaction
- kb
- kilobase(s)
- 10,11-DiHN
- 10,11-dihydroxynonadecanoic acid
- tR
- retention time
- RT
- reverse transcription
- DR-n
- direct repeat spaced by n nucleotides
- TCPOBOP
- 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene.
- Received January 19, 2010.
- Accepted April 6, 2010.
- U.S. Government work not protected by U.S. copyright
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