Effect of pyrazole and dexamethasone administration on cytochrome P450 2E1 and 3A isoforms in rat liver and kidney: lack of specificity of p-nitrophenol as a substrate of P450 2E1.
The induction effects of pyrazole and dexamethasone (known to be specific to P450 2E1 and 3A enzymes, respectively), given alone or simultaneously, were studied in rat liver and kidney microsomes. Pyrazole treatment induced the catalytic activity and the amount of P450 2E1 enzyme in both organs. Immunoreactive P450 2E1 and 4-nitrophenol 2-hydroxylation increased 8- and 13-fold, respectively (versus control), in the kidney, but only 2.4- and 2.7-fold (versus control) in the liver after pyrazole treatment. As assessed by nifedipine oxidation activity, dexamethasone treatment increased the P450 3A catalytic activity approximately 4-fold (versus control) in the liver, but not in the kidney, suggesting that P450 3A was not inducible in the kidney. Pyrazole decreased P450 3A activity in the liver but did not modify it in the kidney. A combination of both chemicals induced both enzymes, but to a lesser extent than treatment with each single chemical compound. Furthermore, the 2-hydroxylation of p-nitrophenol, considered one of the most specific substrates for monitoring the level of P450 2E1, was mediated also by P450 3A, at least in dexamethasone-treated rats. Finally, this experimental work demonstrated that P450 3A induction is organ-specific, and it also demonstrated the lack of specificity of p-nitrophenol as a P450 2E1 substrate.
Zerilli
A
A
Laboratoires de Biochimie-Nutrition, EA-948, Faculté de Médecine, Brest, France.
Lucas
D
D
Dreano
Y
Y
Picart
D
D
Berthou
F
F
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009596:Nitrophenols / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D009596:Nitrophenols; D011720:Pyrazoles; C031280:pyrazole; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C024836:4-nitrophenol