3,5-Diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine inactivates rat liver cytochrome P-450c, but not its orthologue, rabbit lung form 6.
Various rat liver cytochrome P-450 (P-450) isozymes are targets for mechanism-based inactivation by 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4- dihydropyridine (4-ethyl DDC). Unlike rat liver, which contains multiple P-450 isozymes, rabbit lung contains only three major isozymes referred to as forms 2, 5, and 6. We have examined the ability of 4-ethyl DDC to destroy P-450 heme in hepatic and pulmonary microsomes from untreated and beta-naphthoflavone (beta NF)-treated rabbits. This compound destroyed 31% of the P-450 in either hepatic microsomal preparation, but was ineffective at lowering P-450 and heme levels in pulmonary microsomes when examined at a range of concentrations (0.45-5.0 mM). These data suggest that rabbit pulmonary P-450 forms 2, 5, and 6 are not targets for destruction by 4-ethyl DDC, despite the ability of this compound to inactivate rat liver P-450c, the orthologue of rabbit lung form 6.
Riddick
D S
DS
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Mackie
J E
JE
Massey
T E
TE
Marks
G S
GS
D000818:Animals; D001571:Benzoflavones / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D014230:Triazoles / Q000633:toxicity; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; D007527:Isoenzymes; D014230:Triazoles; C030826:3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine; C033020:1-aminobenzotriazole; D006418:Heme; D019324:beta-Naphthoflavone; D003997:Dicarbethoxydihydrocollidine