Expression of cytochrome P450 2A5 in a glucose-6-phosphate dehydrogenase-deficient mouse model of oxidative stress.
Murine hepatic cytochrome P450 2A5 (CYP2A5), unlike most CYP enzymes, is upregulated during hepatitis and hepatotoxic conditions, but the common stimulus for its induction remains unknown. We investigated the involvement of oxidative stress in the regulation of CYP2A5 expression using an oxidative stress-sensitive glucose-6-phosphate dehydrogenase (G6PD)-deficient mouse model. Treatment of deficient and wild-type mice with the prototypical CYP2A5-inducer pyrazole for 72h led to a significantly greater degree of induction of CYP2A5 mRNA, protein and activity in deficient mice, with the greatest increase observed in animals homozygous for the deficiency. However, markers of oxidative stress including protein carbonyl, 8-hydroxydeoxyguanosine, malondiadehyde and 4-hydroxyalkenal levels were unaltered with pyrazole treatment. Furthermore, CYP2A5 expression was not altered in G6PD-deficient mice treated with the pro-oxidant menadione whereas DNA, lipid, and protein markers of oxidative stress were significantly increased. The antioxidant polyethylene glycol-conjugated catalase, while decreasing oxidative stress in menadione-treated mice, did not prevent the induction of CYP2A5 by pyrazole. Finally, the ER stress marker protein, GRP78, was increased following pyrazole treatment in G6PD-deficient compared to wild-type mice. These findings do not support a central role for generalized cellular oxidative stress in the regulation of CYP2A5 and suggest that additional factors related to G6PD-deficiency, such as ER stress, may be involved.
Nichols
Kathleen D
KD
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
Kirby
Gordon M
GM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000494:pharmacology; D050050:Protein Carbonylation; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology
D000975:Antioxidants; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D011720:Pyrazoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C070295:catalase-polyethylene glycol; D014810:Vitamin E; C031280:pyrazole; D011092:Polyethylene Glycols; D024483:Vitamin K 3; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006899:Mixed Function Oxygenases; D005954:Glucosephosphate Dehydrogenase; D002374:Catalase; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D003849:Deoxyguanosine