Oxidation of dihydropyridine calcium channel blockers and analogs by human liver cytochrome P-450 IIIA4

A series of 21 different 4-substituted 2,6-dimethyl-3-(alkoxycarbonyl)-1,4-dihydropyridines was considered with regard to oxidation to pyridine derivatives by human liver microsomal cytochrome P-450 (P-450). Antibodies raised against P-450 IIIA4 inhibited the microsomal oxidation of nifedipine and f...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 34; no. 6; pp. 1838 - 1844
Main Authors:	Guengerich, F. Peter, Brian, William R, Iwasaki, Masahiko, Sari, Marie Agnes, Baeaernhielm, Catharina, Berntsson, Peder
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-06-1991
Subjects:	Biological and medical sciences Calcium Channel Blockers - chemistry Cardiovascular system Chromatography, High Pressure Liquid Cimetidine - pharmacology Cytochrome P-450 Enzyme System - metabolism Dihydropyridines - chemistry Felodipine - antagonists & inhibitors Humans Kinetics Medical sciences Microsomes, Liver - enzymology Miscellaneous Nifedipine - antagonists & inhibitors Norpregnenes - pharmacology Oxidation-Reduction Pharmacology. Drug treatments Human Enzyme Isozyme Cytochrome P450 Liver Calcium antagonist Oxidation Metabolism In vitro Dihydropyridine derivative
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Summary:	A series of 21 different 4-substituted 2,6-dimethyl-3-(alkoxycarbonyl)-1,4-dihydropyridines was considered with regard to oxidation to pyridine derivatives by human liver microsomal cytochrome P-450 (P-450). Antibodies raised against P-450 IIIA4 inhibited the microsomal oxidation of nifedipine and felodipine to the same extent, as did cimetidine and the mechanism-based inactivator gestodene. Gestodene was approximately 10(3) times more effective an inhibitor than cimetidine, on a molar basis. When rates of oxidation of the 1,4-dihydropyridines were compared to each other in different human liver microsomal preparations, all were highly correlated with each other with the exceptions of a derivative devoid of a substituent at the 4-position and an N1-CH3 derivative. A P-450 IIIA4 cDNA clone was expressed in yeast and the partially purified protein was used in reconstituted systems containing NADPH-cytochrome P-450 reductase and cytochrome b5. This system catalyzed the oxidation of all of the 1,4-dihydropyridines except the two for which poor correlation was seen in the liver microsomes. Principal component analysis supported the view that most of these reactions were catalyzed by the same enzyme in the yeast P-450 IIIA4 preparation and in the different human liver microsomal preparations, or by a closely related enzyme showing nearly identical properties of catalytic specificity and regulation. The results indicate that the enzyme P-450 IIIA4 is probably the major human catalyst involved in the formal dehydrogenation of most but not all 1,4-dihydropyridine drugs.
Bibliography:	ark:/67375/TPS-3Q65XH0Q-B istex:58744C75F4EEEB44B021E9C8F2324D795A603FC6 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00110a012