Differential xenobiotic induction of CYP2A5 in mouse liver, kidney, lung, and olfactory mucosa.
The effects of pyrazole, which is known to induce hepatic cytochrome P4502A5 (CYP2A5) through posttranscriptional mechanisms, on the level of CYP2A5 in liver and extrahepatic tissues were examined in this study. Intraperitoneal administration of pyrazole at 200 mg/kg for 3 days induced CYP2A4/5 mRNAs and proteins and microsomal coumarin 7-hydroxylation activity in liver and kidney of C57BL/6 mice. A marginal increase (30%) in CYP2A4/5 mRNAs was also observed in the olfactory mucosa but not in the lung, and no increase in CYP2A4/5 proteins or microsomal coumarin 7-hydroxylation activity was observed in either the olfactory mucosa or lung. CYP2A4/5 proteins were not detected on immunoblots in other tissues examined, including breast, bone marrow, testis, prostate, ovary, and uterus from control or pyrazole-treated mice. On the other hand, pyrazole treatment induced CYP2E1 in the olfactory mucosa as well as in liver and kidney, indicating that the olfactory mucosa was exposed to pyrazole. The lack of CYP2A inducibility in the olfactory mucosa was also observed for several other known inducers of hepatic CYP2A5, including cobaltous chloride, stannous chloride, griseofulvin, thioacetamide, and aminotriazole. These results suggest that the mechanisms involved in the induction of hepatic and renal CYP2A5 by pyrazole and other xenobiotic compounds may be tissue-specific.
Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA.
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D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003035:Cobalt / Q000494:pharmacology; D003374:Coumarins / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D015342:DNA Probes; D004790:Enzyme Induction; D006118:Griseofulvin / Q000494:pharmacology; D015151:Immunoblotting; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000096:biosynthesis*; D009831:Olfactory Mucosa / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013379:Substrate Specificity; D013853:Thioacetamide / Q000494:pharmacology; D017971:Tin Compounds / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology*
D003374:Coumarins; D015342:DNA Probes; D007527:Isoenzymes; D011720:Pyrazoles; D012333:RNA, Messenger; D017971:Tin Compounds; D015262:Xenobiotics; D013853:Thioacetamide; C023599:stannous chloride; D006118:Griseofulvin; D003035:Cobalt; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; C018021:cobaltous chloride; D000640:Amitrole