Effects of cigarette smoke and a heterocyclic amine, MeIQx on cytochrome P-450, mutagenic activation of various carcinogens and glucuronidation in rat liver.
In order to elucidate the mechanism underlying enhancement by cigarette smoke (CS) of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced rat hepatocarcinogenesis, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of various carcinogens and UDP-glucuronyltransferase (UDPGT) activities were assayed in male F344 rats. Immunoblot analyses for microsomal CYP proteins revealed induction of CYP1A1 and constitutive CYP1A2 (2.3- to 2.7-fold), but not CYP2B1/2, 2E1 or 3A2, by CS exposure for 1, 12 or 16 weeks using a Hamburg type II smoking machine; the enhancement of CYP1A2 was 4.7-5.7 times that of CYP1A1. CS exposure also elevated the mutagenic activities of MeIQx and five other heterocyclic amines (HCAs) 1.4- to 3.7-fold, but not those of benzo[a]pyrene (BP) and aflatoxin B(1) in strain TA98 and N-nitrosodimethylamine, N-nitrosopyrrolidine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in strain TA100. In contrast, feeding 300 p.p.m. MeIQx in the diet for 1 or 16 weeks produced no significant alterations in the levels of these CYP species and mutagenic activities. However, i.g. administration of 50 or 100 mg/kg MeIQx in a single dose selectively increased CYP1A1 and 1A2 (2.6-fold) levels and mutagenic activities of five HCAs (1.7- to 3.3-fold), but not BP. On the other hand, feeding of MeIQx for 16 weeks enhanced UDPGT activities towards 4-nitrophenol and testosterone (2.9- and 1.5-fold, respectively), but not bilirubin, while CS exposure induced that towards 4-nitrophenol (1.6-fold); combined treatment with CS and MeIQx showed a summation effect on induction of UDPGT1A6 activity (3.5-fold). Consequently, these results demonstrate that CS and MeIQx have a bifunctional action, with similar induction patterns of specific CYP proteins, mutagenic activity and UDPGT activity. In conjunction with the finding of N-hydroxy-MeIQx being a poor substrate for rat liver UDPGT, our results clearly indicate that enhancement by CS of MeIQx-induced hepatocarcinogenesis in F344 rats can be attributed to an increase in metabolic activation of MeIQx by hepatic CYP1A2 during the initiation phase.
Mori
Yukio
Y
Laboratory of Radiochemistry, Gifu Pharmaceutical University, 6-1 Mitahora-higashi 5-chome, Gifu 502-8585, Japan. ymori@gifu-pu.ac.jp
Koide
Akihiro
A
Kobayashi
Yoshinori
Y
Furukawa
Fumio
F
Hirose
Masao
M
Nishikawa
Akiyoshi
A
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects*; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D003043:Cocarcinogenesis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000378:metabolism*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011810:Quinoxalines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012906:Smoke / Q000009:adverse effects*; D013047:Specific Pathogen-Free Organisms; D013250:Steroid Hydroxylases / Q000378:metabolism; D013379:Substrate Specificity
D002273:Carcinogens; D007093:Imidazoles; D008565:Membrane Proteins; D011810:Quinoxalines; D012906:Smoke; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; D014453:Glucuronosyltransferase