Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats.
We reported earlier that exposure of rats to 3-methylcholanthrene (MC) causes sustained induction of hepatic cytochrome P450 (CYP)1A expression for up to 45 days by mechanisms other than persistence of the parent MC (Moorthy, J. 2000. Pharmacology. Exp. Ther. 294, 313-322). The CYP1A genes are members of the Ah gene battery that also encode CYP1B1 and phase II enzymes such as glutathione S-transferase (GST-alpha), UDP glucuronyl transferase (UGT)1A, NAD(P)H (nicotinamide adenine dinucleotide phosphate, reduced):quinone oxidoreductase I (NQO1), aldehyde dehydrogenase (ALDH), etc. Therefore, in this investigation, we tested the hypothesis that MC elicits persistent induction of CYP1B1 and phase II genes, which are in part regulated by the Ah receptor (AHR). Female Sprague-Dawley rats were treated with MC (100 mumol/kg), ip, once daily for 4 days, and expression of CYP1B1 and several phase II (e.g., GST-alpha, NQO1) genes and their corresponding proteins were determined in lung and liver. The major finding was that MC persistently induced (3- to 10-fold) the expression of several phase II enzymes, including GST-alpha, NQO1, UGT1A1, ALDH, and epoxide hydrolase in both tissues for up to 28 days. However, MC did not elicit sustained induction of CYP1B1. Our results thus support the hypothesis that MC elicits coordinated and sustained induction of phase II genes presumably via persistent activation of the AHR, a phenomenon that may have implications for chemical-induced carcinogenesis and chemopreventive strategies in humans.
Kondraganti
Sudha R
SR
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Jiang
Weiwu
W
Jaiswal
Anil K
AK
Moorthy
Bhagavatula
B
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D065633:Cytochrome P-450 CYP1B1; D004790:Enzyme Induction / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D008748:Methylcholanthrene / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D000444:Aldehyde Dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases; D002273:Carcinogens; D065633:Cytochrome P-450 CYP1B1; D004851:Epoxide Hydrolases; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D007527:Isoenzymes; D008748:Methylcholanthrene; D016660:NAD(P)H Dehydrogenase (Quinone); D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C585496:CYP1B1 protein, human; C585499:Cyp1b1 protein, rat; C507703:NQO1 protein, rat; C119995:glutathione S-transferase alpha