CYP2J2 is a member of the cytochrome P450 (CYP) family of monooxygenases, and, in humans, is the sole member of the CYP2J subfamily [Article:9570962]. Specifically, CYP2J2 is an epoxygenase that catalyzes epoxide formation at the site of a carbon-carbon double bond in the substrate, as do other CYP epoxygenases, such as CYP2C8 and CYP2C9 [Article:15466638].
The therapeutic agents ebastine [Article:16842392], astemizole, terfenadine, diclofenac, and bufurarol are metabolized by CYP2J2 [Article:15861034]. A recent study screening 139 marketed therapeutic agents and compounds identified albendazole, amiodarone, cyclosporine A, danazol, mesoridazine, nabumetone, tamoxifen, and thioridazine as CYP2J2 substrates [Article:19923256]. These findings demonstrate the ability of CYP2J2 to metabolize structurally diverse compounds. The substrates identified for CYP2J2 were also metabolized by CYP3A4, but with differences in regioselectivity [Article:19923256]. For large compounds, CYP2J2 metabolism was more restricted to a single site, as compared with CYP3A4, which metabolized substrates at multiple sites [Article:19923256]. A study in microsomes from human livers and human small intestines investigated the metabolism of astemizole by CYP2J2 [Article:12386130]. 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 [Article:12386130]. A follow-up study found an inhibition of alpha-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 [Article:12851038].
AA and linoleic acid (LA) are endogenous substrates of CYP2J2 [Article:15466638], [Article:11901223]. 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 [Article:10681399]. EETs have been shown to possess many biologically relevant properties, such as inducing membrane hyperpolarization and vasodilation, reducing inflammation via inhibition of transcription factor NF-kB, and increasing fibrinolytic activity (reviewed in [Article:11451964]). CYP2J2-derived EETs have been shown to be cardioprotective following ischemia [Article:18973759] and after doxorubicin treatment [Article:19429816] in animal studies using a transgenic mouse model over-expressing the human CYP2J2 isoform. How these findings translate into humans needs to be further investigated.
CYP2J2 activates the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha), a controller of lipid metabolism and inflammation, in vitro and in vivo [Article:19823578]. A CYP2J2 cDNA was cloned in 1996 by Wu et al. [Article:8631948], and the CYP2J2 genomic region was cloned in 2002 by King et al. [Article:11901223]. CYP2J2 was mapped to human chromosome 1 [Article:9570962] and the genomic region spans approximately 40 kb [Article:11901223], encoding a 1.9 kb transcript from which a 502 amino acid protein with a molecular mass of 57.7 kilodaltons is produced [Article:8631948]. The CYP2J2 gene, like other CYP2 family genes, is comprised of 9 exons and 8 introns [Article:11901223]. Four binding site consensus sequences for the SP1 transcription factor are found in the wild-type CYP2J2 promoter [Article:15466638]. As expected for members of the CYP family, there is a heme-binding motif in the CYP2J2 predicted protein sequence [Article:8631948].
The presence of CYP2J2 protein in microsomes [Article:8631948] is indicative of its subcellular localization to the endoplasmic reticulum (ER). CYP2J2 is expressed at high levels in the heart, particularly in cardiac myocytes and endothelial cells in coronary arteries [Article:8631948], [Article:10455056]. Other tissues, including the liver, kidney, lung, pancreas, and gastrointestinal tract, also express CYP2J2 [Article:11901223]. CYP2J2 showed selective distribution in different brain regions [Article:12772594], [Article:19359404]. All of these tissues also exhibit fetal expression of CYP2J2 [Article:16868033].
Due 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 [Article:19550113]. Inhibitors of CYP2J2 related to the drug terfenadine showed effectiveness as antitumor agents in in vitro assays and in murine xenograft models [Article:19289568]. Increased CYP2J2 expression has been observed in tumor samples from patients with advanced epithelial ovarian cancer [Article:17908963], and in vitro studies showed that overexpression of CYP2J2 promoted human cancer metastasis [Article:17638876].
Note: The CYP2J2 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
|Citation||PharmGKB summary: cytochrome P450, family 2, subfamily J, polypeptide 2: CYP2J2. Pharmacogenetics and genomics. 2010. Berlin Dorit S, Sangkuhl Katrin, Klein Teri E, Altman Russ B.|
Submitted by Dorit Berlin
Updated by Dorit Berlin, Katrin Sangkuhl
arachidonic acid, linoleic acid