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J. Biol. Chem., Vol. 276, Issue 27, 25467-25479, July 6, 2001
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From the A cDNA encoding a new cytochrome
P450 was isolated from a mouse brain library. Sequence analysis reveals
that this 1,958-base pair cDNA encodes a 57-58-kDa 502-amino acid
polypeptide that is 70-91% identical to CYP2J subfamily P450s and is
designated CYP2J9. Recombinant CYP2J9 was co-expressed with
NADPH-cytochrome P450 oxidoreductase (CYPOR) in Sf9
cells using a baculovirus system. Microsomes of
CYP2J9/CYPOR-transfected cells metabolize arachidonic acid to
19-hydroxyeicosatetraenoic acid (HETE) thus CYP2J9 is enzymologically
distinct from other P450s. Northern analysis reveals that CYP2J9
transcripts are present at high levels in mouse brain. Mouse brain
microsomes biosynthesize 19-HETE. RNA polymerase chain reaction
analysis demonstrates that CYP2J9 mRNAs are widely distributed in
brain and most abundant in the cerebellum. Immunoblotting using an
antibody raised against human CYP2J2 that cross-reacts with CYP2J9
detects a 56-kDa protein band that is expressed in cerebellum and other
brain segments and is regulated during postnatal development. In
situ hybridization of mouse brain sections with a CYP2J9-specific riboprobe and immunohistochemical staining with the anti-human CYP2J2
IgG reveals abundant CYP2J9 mRNA and protein in cerebellar Purkinje
cells. Importantly, 19-HETE inhibits the activity of recombinant
P/Q-type Ca2+ channels that are known to be expressed
preferentially in cerebellar Purkinje cells and are involved in
triggering neurotransmitter release. Based on these data, we conclude
that CYP2J9 is a developmentally regulated P450 that is abundant in
brain, localized to cerebellar Purkinje cells, and active in the
biosynthesis of 19-HETE, an eicosanoid that inhibits activity of
P/Q-type Ca2+ channels. We postulate that CYP2J9
arachidonic acid products play important functional roles in the brain.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF336850. The sequence reported in this paper was submitted to the
Committee on Standardized Cytochrome P450 Nomenclature and has been designated CYP2J9.
Cytochrome P450 CYP2J9, a New Mouse Arachidonic Acid
-1
Hydroxylase Predominantly Expressed in Brain*
,,,,,,
,
Division of Intramural Research, NIEHS,
National Institutes of Health, Research Triangle Park,
North Carolina 27709, the § Department of Medicine,
Vanderbilt University, Nashville, Tennessee 37232, the
¶ Inorganic Carcinogenesis Section, NCI at NIEHS, National
Institutes of Health, Research Triangle Park, North Carolina, 27709, the Department of Biochemistry, University of Texas Southwestern
Medical Center, Dallas, Texas 75235, and the ** Department of
Pharmacology, University of North Carolina,
Chapel Hill, North Carolina 27599
*
This work was supported by National Institutes of
Health Grants P01-DK38226 (to M. D. B.), GM-31278 (to J. R. F.),
and HL49449 (to R. L. R.) and the NIEHS Division of Intramural
Research.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: Laboratory of
Pulmonary Pathobiology, NIEHS, National Institutes of Health, Bldg. 101, Rm. D236, 111 T.W. Alexander Dr., Research Triangle Park, NC
27709. Tel.: 919-541-1169; Fax: 919-541-4133; E-mail:
zeldin@niehs.nih.gov.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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