Effect of ethanol treatment on metabolic activation and detoxification of esophagus carcinogenic N-nitrosamines in rat liver.
In order to elucidate the mechanism underlying enhancement by ethanol of N-nitrosodiethylamine (DEN)- and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of several N-nitrosamines and three kinds of UDP-glucuronyltransferase (UDPGT) activities were assayed in F344 rats. Immunoblot analyses of microsomal CYP proteins revealed induction of CYP2E1 (approximately 2-fold), but not CYP2B1/2, 1A1/2 or 3A2, by treatment with 10% ethanol in the drinking water for 2 weeks. In contrast, s.c. treatment with 0.5 mg/kg NMBA three times per week for 2 weeks produced no significant alterations in the levels of these CYP species. Ethanol treatment also elevated the mutagenic activities of N-nitrosodimethylamine (DMN), DEN and N-nitrosopyrrolidine (NPYR) in strain TA100 up to 2.1-, 1.6- and 2.3-fold above each control, respectively. However, this was not the cases for four N-nitrosamines, including NMBA, in strain TA100 and two heterocyclic amines and aflatoxin B(1) in strain TA98. In addition, ethanol did not affect UDPGT activities towards 4-nitrophenol, bilirubin and testosterone. Hepatic CYP species responsible for mutagenic activation of selected N-nitrosodialkylamines were confirmed by use of specific CYP inducers and inhibitors with the liver from F344 and Wistar rats, indicating that DMN, DEN and NMBA are selectively activated by CYP2E1, predominantly by CYP2E1 with a slight contribution by CYP2B2 and selectively by CYP2B1/2, respectively. These results demonstrate that ethanol exerts an enhancing effect on mutagenic activation by CYP2E1 of DMN, DEN and NPYR, but does not affect that of NMBA and the other carcinogens by CYP2B1/2, 1A1/2 and 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, this suggests that enhancement by ethanol of DEN-induced esophageal carcinogenesis in F344 rats can be attributed to an increase in hepatic activation during the initiation phase, but that of NMBA-induced tumorigenesis is not attributable to metabolic activation and inactivation via glucuronidation in liver.
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
Morimura
Keiichirou
K
Kaneko
Masahiro
M
Fukushima
Shoji
S
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D003720:Densitometry; D004052:Diethylnitrosamine; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D004938:Esophageal Neoplasms / Q000139:chemically induced; D000431:Ethanol; D014453:Glucuronosyltransferase / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009153:Mutagens; D009154:Mutation; D009602:Nitrosamines; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012997:Solvents
D002273:Carcinogens; D009153:Mutagens; D009602:Nitrosamines; D012997:Solvents; D004052:Diethylnitrosamine; D000431:Ethanol; C014707:nitrosobenzylmethylamine; D019392:Cytochrome P-450 CYP2E1; D014453:Glucuronosyltransferase; D004128:Dimethylnitrosamine