Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors
| Autor: | Xuandai Nguyen, John R. Falck, Michal L. Schwartzman, Komandla Malla Reddy, Mong Heng Wang |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Gene isoform Insecta Physiology Hydroxylation Catalysis Cell Line Mixed Function Oxygenases chemistry.chemical_compound 8 11 14-Eicosatrienoic Acid Cytochrome P-450 Enzyme System Physiology (medical) Hydroxyeicosatetraenoic Acids Animals Protein Isoforms Enzyme Inhibitors CYP2C8 Arachidonic Acid biology Fatty Acids Cytochrome P450 Metabolism 20-Hydroxyeicosatetraenoic acid Recombinant Proteins In vitro Rats Kinetics Eicosanoid chemistry Biochemistry biology.protein Female Arachidonic acid Cytochrome P-450 CYP4A Oxidation-Reduction |
| Zdroj: | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 276:R1691-R1700 |
| ISSN: | 1522-1490 0363-6119 |
| Popis: | 20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and -4A8 cDNAs, using baculovirus and Sf 9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM−1⋅ min−1for CYP4A1 was followed by 72 and 22 nM−1⋅ min−1for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω-hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform-specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20-HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12-epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone. |
| Databáze: | OpenAIRE |
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