Characterization of pyrazole and 4-methylpyrazole induction of cytochrome P4502E1 in rat kidney.
Pyrazole and 4-methylpyrazole induce cytochrome P4502E1 (P4502E1) in the liver. It is not known whether induction occurs in nonhepatic tissue such as kidney and lung. Rats were treated with saline, pyrazole or 4-methylpyrazole and assayed for the activity and content of P4502E1 and mRNA in liver, lung and kidney. Treatment with these agents resulted in increases in P4502E1 content as detected by immunoblots in liver and kidney, but not lung, microsomes. Oxidation of relatively specific substrates for P4502E1 was also significantly increased with liver and kidney microsomes after pyrazole or 4-methylpyrazole treatment. P4502E1 mRNA levels in liver, kidney and lung were not increased by treatment with pyrazole or 4-methylpyrazole. Associated with the induction of P4502E1 was an elevated production of reactive oxygen intermediates such as superoxide radical and H2O2 by kidney and liver, but not lung. microsomes. Lipid peroxidation induced by CCI4 was also increased with kidney microsomes after treatment with pyrazole or 4-methylpyrazole. Anti-P4502E1 IgG inhibited the increased oxidation of substrates and the increased production of H2O2 by the kidney microsomes found after treatment with pyrazole and 4-methylpyrazole. These results show that pyrazole and 4-methylpyrazole, which induce P4502E1 in liver, are also effective in inducing this enzyme in the kidney, whereas the lung is not sensitive to induction by these agents. The mechanism of induction of kidney P4502E1, similarly to that of liver, appears to reflect a post-transcriptional effect-probably stabilization of the protein against degradation.
Department of Biochemistry, Mount Sinai School of Medicine, New York, New York.
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D000818:Animals; D001483:Base Sequence; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D000077604:Fomepizole; D006861:Hydrogen Peroxide / Q000378:metabolism; D007074:Immunoglobulin G; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
D007074:Immunoglobulin G; D011720:Pyrazoles; D012333:RNA, Messenger; D013481:Superoxides; C031280:pyrazole; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating