CYP2C44, a new murine CYP2C that metabolizes arachidonic acid to unique stereospecific products.
The human CYP2Cs have been studied extensively with respect to the metabolism of clinically important drugs and endogenous chemicals such as arachidonic acid (AA). Five members of the mouse CYP2C family have previously been described that metabolize arachidonic acid into regio- and stereospecific epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids, which have many important physiological roles. Herein, we describe the cloning and characterization of a new mouse cytochrome P450 (P450), CYP2C44, which has the lowest homology with other known mouse CYP2Cs. Western blotting and real-time polymerase chain reaction detected CYP2C44 mRNA and protein in liver >> kidney > adrenals. Kidney contained approximately 10% of the CYP2C44 mRNA content of liver. CYP2C44 metabolized AA to unique stereospecific products, 11R,12S-EET and 8R, 9S-EET, which are similar to those produced by rat CYP2C23. CY2C23 is highly expressed in rat kidney and has been suggested to be important in producing compensatory renal artery vasodilation in response to salt-loading in this species. Immunohistochemistry showed the presence of CYP2C44 in hepatocytes, biliary cells of the liver, and the proximal tubules of the kidney. Unlike mouse CYP2C29, CYP2C38, and CYP2C39, CYP2C44 did not metabolize the common CYP2C substrate tolbutamide. CYP2C44 was not induced by phenobarbital or pregnenolone-16alpha-carbonitrile, two prototypical inducers of hepatic P450s. The presence of CYP2C44 in mouse liver, kidney, and adrenals and the unique stereospecificity of its arachidonic acid metabolites are consistent with the possibility that it may have unique physiological roles within these tissues, such as modulation of electrolyte transport or vascular tone.
DeLozier
Tracy C
TC
Laboratory of Pharmacology, National Institute of Environmental Health Sciences, P.O. Box 12233, 111 T.W. Alexander Drive, Building 101, Research Triangle Park, NC 27709.
Tsao
Cheng-Chung
CC
Coulter
Sherry J
SJ
Foley
Julie
J
Bradbury
J Alyce
JA
Zeldin
Darryl C
DC
Goldstein
Joyce A
JA
D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D003001:Cloning, Molecular; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014044:Tolbutamide / Q000378:metabolism
C000717351:Cyp2c23 protein, rat; D018076:DNA, Complementary; C400322:cytochrome P-450 CYP2C subfamily; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; C492667:Cyp2c23 protein, mouse; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2