Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels.
Glutathione S-transferases and the cytochrome P450 system have been proposed for the vascular biotransformation systems in the metabolic activation of organic nitrates. The present study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate.
Minamiyama
Y
Y
Department of Pathology, Faculty of Medicine, Okayama University, Shikatacho, Japan.
Takemura
S
S
Akiyama
T
T
Imaoka
S
S
Inoue
M
M
Funae
Y
Y
Okada
S
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003331:Coronary Vessels / Q000201:enzymology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004699:Endocardium / Q000201:enzymology; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014162:Transfection
D000906:Antibodies; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; D007548:Isosorbide Dinitrate; D007654:Ketoconazole