CYP2J Subfamily Cytochrome P450s in the Gastrointestinal Tract: Expression, Localization, and Potential Functional Significance

Abstract

Our laboratory recently described a new human cytochrome P450 arachidonic acid epoxygenase (CYP2J2) and the corresponding rat homologue (CYP2J3), both of which were expressed in extrahepatic tissues. Northern analysis of RNA prepared from the human and rat intestine demonstrated that CYP2J2 and CYP2J3 mRNAs were expressed primarily in the small intestine and colon. In contrast, immunoblotting studies using a polyclonal antibody raised against recombinant CYP2J2 showed that CYP2J proteins were expressed throughout the gastrointestinal tract. Immunohistochemical staining of formalin-fixed, paraffin-embedded intestinal sections using anti-CYP2J2 IgG and avidin-biotin-peroxidase detection revealed that CYP2J proteins were present at high levels in nerve cells of autonomic ganglia, epithelial cells, intestinal smooth muscle cells, and vascular endothelium. The distribution of this immunoreactivity was confirmed by in situ hybridization using a CYP2J2-specific antisense RNA probe. Microsomal fractions prepared from human jejunum catalyzed the NADPH-dependent metabolism of arachidonic acid to epoxyeicosatrienoic acids as the principal reaction products. Direct evidence for the in vivo epoxidation of arachidonic acid by intestinal cytochrome P450 was provided by documenting, for the first time, the presence of epoxyeicosatrienoic acids in human jejunum by gas chromatography/mass spectrometry. We conclude that human and rat intestine contain an arachidonic acid epoxygenase belonging to the CYP2J subfamily that is localized to autonomic ganglion cells, epithelial cells, smooth muscle cells, and vascular endothelium. In addition to the known effects on intestinal vascular tone, we speculate that CYP2J products may be involved in the release of intestinal neuropeptides, control of intestinal motility, and/or modulation of intestinal fluid/electrolyte transport.

Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2

“…Much less is known about more recently discovered human CYPs such as CYP2J2 [2,11,12]. This cytochrome seems to be primarily expressed in heart [11]; it has also been found in kidney, liver, lung and the gastrointestinal tract [11][12][13][14]. CYP2J2 has been found to catalyze the epoxidation of arachidonic acid to four cisepoxyeicosatrienoic acids (EETs), with regio-and stereo-selectivities that match those of the EETs isolated from heart tissue [11].…”

Contribution of Rat Pulmonary Metabolism to the Elimination of Lidocaine, Midazolam, and Nifedipine

“…The pulmonary intrinsic clearance values of lidocaine, midazolam, and nifedipine in rat microsomes were lower than their hepatic intrinsic clearance, showing that there was an organ difference in metabolism between the liver and lung. Our results support the importance of the estimation of pulmonary metabolism to predict the total clearance more accurately.The lung has a variety of drug-metabolizing enzymes, such as the CYP1A, 2A, 2B, 2E, 2F, 2J, 3A, and 4B families (Dees et al, 1982;Domin et al, 1986;de Waziers et al, 1990;Nhamburo et al, 1990;Ueno and Gonzalez, 1990;Debri et al, 1995;Zeldin et al, 1996). The lung is an efficient organ for extracting drugs from the blood circulation because all cardiac output goes through it (Perreault et al, 1993).…”

Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species

“…Samples were dried under a N 2 stream, separated by reverse-phase HPLC, and quantified by on-line liquid scintillation using a Radiomatic Flo-One ,(3-detector (Radiomatic Instruments, Tampa, FL) as previously described (2). Determination of the regiochemistry of epoxidation required greater reverse-phase separation and was performed as previously described (34). Formation of each regioisomer was calculated as the sum of the EET and the DHET and, in the case of the 5,6-olefin, the S-lactone as well.…”