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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pharmacogenet Genomics. Author manuscript; available in PMC May 1, 2012.
Published in final edited form as:
PMCID: PMC3086341
NIHMSID: NIHMS286413
PharmGKB summary: cytochrome P450, family 2, subfamily J, polypeptide 2: CYP2J2
Dorit S. Berlin,a Katrin Sangkuhl,a Teri E. Klein,a and Russ B. Altmanab
aDepartment of Genetics, Stanford University, Stanford, California, USA
bDepartment of Bioengineering, Stanford University, Stanford, California, USA
Correspondence to Teri E. Klein, PhD, Department of Genetics, Stanford University Medical Center, 1501 California Avenue, Palo Alto, Stanford, CA 94305-5120, USA Tel: + 1 650 725 0659; fax: + 1 650 725 3863; feedback/at/pharmgkb.org
Keywords: CYP2J, CYP2J2, CYP2J2*7, epoxygenase, PharmGKB, rs890293
CYP2J2 is a member of the cytochrome P450 (CYP) family of monooxygenases, and, in humans, is the sole member of the CYP2J subfamily [1]. Specifically, CYP2J2 is an epoxygenasethat catalyzes epoxideformation at thesite of a carbon–carbon double bond in the substrate, as other CYP epoxygenases do, such as CYP2C8 and CYP2C9 [2]. The therapeutic agents ebastine [3], astemizole, terfenadine, diclofenac, and bufurarol are metabolized by CYP2J2 [4]. A recent study, screening 139 marketed therapeutic agents and compounds, have identified albendazole, amiodarone, cyclosporine A, danazol, mesoridazine, nabumetone, tamoxifen, and thioridazine as CYP2J2 substrates [5]. These findings show the ability of CYP2J2 to metabolize structurally diverse compounds. The substrates identified for CYP2J2 were also metabolized by CYP3A4, but with differences in regioselectivity [5]. For large compounds, CYP2J2 metabolism was more restricted to a single site, compared with CYP3A4, which metabolized substrates at multiple sites [5]. A study of microsomes from human livers and human small intestines investigated the metabolism of astemizole by CYP2J2 [6]. This study found that the CYP2J2 substrates arachidonic acid (AA) and ebastine strongly inhibited astemizole O-demethylation in microsomes from human small intestines and in in-vitro experiments with recombinant CYP2J2 [6]. A follow-up study found an inhibition of α-naphthoflavone, ketoconazole, troglitazone, tranylcypromine, ebastine, and terfenadine on the rate of astemizole O-demethylation in human small intestinal microsomes and on the rate of astemizole O-demethylation in recombinant CYP2J2 microsomes [7].
AA and linoleic acid (LA) are endogenous substrates of CYP2J2 [2,8]. CYP epoxygenases catalyze the metabolism of AA to four regioisomeric epoxyeicosatrienoic acids (EETs): 14,15-EET, 11,12-EET, 5,6-EET, and 8,9-EET [9]. EETs have been shown to possess many biologically relevant properties, such as inducing membrane hyperpolarization and vasodilation, reducing inflammation by inhibition of transcription factor nuclear factor-κB, and increasing fibrinolytic activity (reviewed in [10]). CYP2J2-derived EETs have been shown to be cardioprotective after ischemia [11] and after doxorubicin treatment [12] in animal studies using a transgenic mouse model over-expressing the human CYP2J2 isoform. How these findings translate into humans needs to be investigated further. CYP2J2 activates the nuclear peroxisome proliferator-activated receptor α, a controller of lipid metabolism and inflammation, in vitro and in vivo [13].
A CYP2J2 cDNA was cloned in 1996 by Wu et al. [14], and the CYP2J2 genomic region was cloned in 2002 by King et al. [8]. CYP2J2 was mapped to human chromosome 1 [1] and the genomic region spans approximately 40 kb [8], encoding a 1.9 kb transcript from which a 502 amino acid protein with a molecular mass of 57.7 kDa was produced [14]. The CYP2J2 gene, like other CYP2 family genes, is composed of nine exons and eight introns [8]. Four binding site consensus sequences for the SP1 transcription factor are found in the wild-type CYP2J2 promoter [2]. As expected for members of the CYP family, there is a heme-binding motif in the CYP2J2 predicted protein sequence [14]. The presence of CYP2J2 protein in microsomes [14] is indicative of its subcellular localization to the endoplasmic reticulum. CYP2J2 is expressed at high levels in the heart, particularly in cardiac myocytes and endothelial cells in coronary arteries [14,15]. Other tissues, including the liver, kidney, lung, pancreas, and gastrointestinal tract, also express CYP2J2 [8]. CYP2J2 showed selective distribution in different brain regions [16,17]. All of these tissues also exhibit fetal expression of CYP2J2 [18].
Owing to its predicted role in cardiovascular health, CYP2J2 has been extensively studied. The role of CYP2J2 in cancer is also being investigated. In-vitro experiments showed a high and selective expression of CYP2J2 in different human tumor tissues and cell lines [19]. Inhibitors of CYP2J2 related to the drug terfenadine showed effectiveness as antitumor agents in in-vitro assays and in murine xenograft models [20]. Increased CYP2J2 expression has been observed in tumor samples from patients with advanced epithelial ovarian cancer [21]; and in-vitro studies showed that overexpression of CYP2J2 promoted human cancer metastasis [22].
Important variants: CYP2J2: G-50T, CYP2J2: G-76T, rs890293, defining single nucleotide polymorphism for CYP2J2*7
Several CYP2J2 variants have been characterized [4,8,18]. The Human Cytochrome P450 Nomenclature Committee recognizes 10 CYP2J2 alleles on its website (http://cypalleles.ki.se). By far, the best studied of these is CYP2J2*7, which was first identified by King et al.[8] in a sequencing project to identify CYP2J2 variants. CYP2J2*7 is the most commonly known functional CYP2J2 variant, occurring at frequencies of 2.1–17% (Table 1). The defining single nucleotide polymorphism (SNP) for CYP2J2*7, rs890293, is located in the proximal promoter of CYP2J2, substituting ‘T’ for ‘G’ found in the wild-type gene [8]. This SNP, located 76 nucleotides upstream of the first nucleotide of the translation start codon and 50 nucleotides upstream of the transcription start site, disrupts a binding site for the SP1 transcription factor [2,8]. In-vitro assays showed that transcription was reduced to 50% in CYP2J2*7 promoter-reporter gene constructs relative to that observed for the wild-type CYP2J2 promoter [2].
Table 1
Table 1
CYP2J2: G-50T allele frequency table
As CYP2J2*7 is the most common functional CYP2J2 polymorphism discovered, many studies have looked for associations between CYP2J2*7 and various diseases and phenotypes. However, because of conflicting results from different studies, there is no clear consensus on the in-vivo effects of CYP2J2*7 yet. Several clinical studies investigated the association of CYP2J2*7 with different cardiovascular and cerebrovascular diseases. The findings are summarized in Table 2.
Table 2
Table 2
CYP2J2*7 association with different disease risks
In addition, a case–control study of a predominately Caucasian population found two CYP2J2 intronic tag SNPs, rs10889160 and rs11572325, associated with increased risk of myocardial infarction [37]. Both the SNPs were in moderate linkage disequilibrium with the CYP2J2*7 allele. Interestingly, rs4388726, the tag SNP in the strongest linkage disequilibrium with the CYP2J2*7 polymorphism, showed no significant association with myocardial infarction [37]. This study found no association between these genetic variations in CYP2J2 and ischemic stroke [37].
Other CYP2J2 alleles
Recombinant CYP2J2 proteins individually engineered to contain the polymorphisms seen in CYP2J2*2, CYP2J2*3, and CYP2J2*6 each exhibited reduced metabolism of AA and LA [8]. Recombinant protein carrying CYP2J2*4 polymorphism showed reduced metabolism of AA only [8]. CYP2J2*5 recombinant protein produced wild-type levels of AA and LA metabolites [8]. Recombinant CYP2J2*8 almost showed a complete loss of enzymatic activity as determined by CYP2J2-catalyzed astemizole O-demethylation and ebastine hydroxylation, whereas recombinant CYP2J2*9 showed enzymatic activities comparable with wild-type CYP2J2 [4]. CYP2J2*10, documented in only one individual, is hypothesized to encode a reduced-function protein [18].
Acknowledgement
PharmGKB is financially supported by the NIH/NIGMS (GM61374).
Footnotes
Present address: Dorit S. Berlin, Coriell Institute for Medical Research, Camden, New Jersey 08103, USA
Online content for the CYP2J2 gene (PA27112) and the very important pharmacogene summary is available at http://www.pharmgkb.org/search/annotatedGene/cyp2j2/.
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