Acute sodium arsenite treatment induces Cyp2a5 but not Cyp1a1 in the C57Bl/6 mouse in a tissue (kidney) selective manner.
Modulation of hepatic and extrahepatic detoxication enzymes Cyp1a1, Cyp2a5, glutathione S-transferse Ya (GSTYa) and NAD(P)H:quinone oxidoreductase (QOR) dependent catalytic activity and mRNA levels were investigated at 1, 2, or 4 days in liver, lung, or kidney of male, adult CD57 Bl/6 mice treated sc with a single dose (85 micromol/kg) of sodium arsenite (As3+). Maximum decreases of total hepatic cytochrome P450 (CYP) monooxygenase content and catalytic activities, occurring at 24 h, corresponded with maximum increases of heme oxygenase (HO-1) in all tissues, as well as maximum plasma total bilirubin. Extrahepatic increases in CYP were observed only in non-AHR dependent isozymes in the kidney, where both Cyp2a5 mRNA and catalytic activity increased maximally 24 h after treatment. In contrast, no significant changes in Cyp2b1/2-dependent PROD or mRNA activity and decreases in Cyp1a1-dependent-EROD activity were noted 1, 2, or 4 days after treatment. Increases in QOR catalytic activities were observed in all tissues examined with increased mRNA in kidney. On the other hand, GSTYa catalytic activity and mRNA increases were only detected in kidney. This study demonstrates the differential modulation of CYP, QOR, and GST-Ya, important drug metabolizing enzymes after acute As3+ administration. The induction of Cyp2a5, QOR, and GSTYa catalytic activity and gene expression occurred primarily in kidney during or shortly after conditions of oxidant stress.
Seubert
John M
JM
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Webb
Christopher D
CD
Bend
John R
JR
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases; D001663:Bilirubin / Q000097:blood; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D005982:Glutathione Transferase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009928:Organ Specificity; D011808:Quinone Reductases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012709:Serum Albumin / Q000032:analysis; D017670:Sodium Compounds / Q000633:toxicity*
D018053:Arsenites; D012333:RNA, Messenger; D012709:Serum Albumin; D017670:Sodium Compounds; C017947:sodium arsenite; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D006419:Heme Oxygenase (Decyclizing); C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D005982:Glutathione Transferase; D001663:Bilirubin