The nuclear receptors constitutive active/androstane receptor and pregnane x receptor activate the Cyp2c55 gene in mouse liver.
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 16alpha-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 (-1679)TGAACCCAGTTGAACT(-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.
Konno
Yoshihiro
Y
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Kamino
Hiroki
H
Moore
Rick
R
Lih
Fred
F
Tomer
Kenneth B
KB
Zeldin
Darryl C
DC
Goldstein
Joyce A
JA
Negishi
Masahiko
M
D000818:Animals; D001483:Base Sequence; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*
D000090702:Constitutive Androstane Receptor; D006893:Hydroxyeicosatetraenoic Acids; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D011285:Pregnenolone Carbonitrile; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C485373:Cyp2c55 protein, mouse; D000072467:Cytochrome P450 Family 2; D010634:Phenobarbital