Alcohol consumption is frequently associated with various
cancers and the enhancement of the metabolic activation of
carcinogens has been proposed as a mechanism underlying this relationship. The
ethanol-induced enhancement of
N-nitrosodiethylamine (DEN)-mediated
carcinogenesis can be attributed to an increase in hepatic activity. However, the mechanism of elevation of
N-nitrosomethylbenzylamine (NMBA)-induced
tumorigenesis remains unclear. To elucidate the mechanism underlying the role of
ethanol in the enhancement of NMBA-induced oesophageal
carcinogenesis, we evaluated the hepatic and extrahepatic levels of the
cytochrome P450 (CYP) and mutagenic activation of
environmental carcinogens by immunoblot analyses and Ames preincubation test, respectively, in F344 rats treated with
ethanol. Five weeks of treatment with 10%
ethanol added to the
drinking water or two intragastric treatments with 50%
ethanol, both resulted in elevated levels of
CYP2E1 (1.5- to 2.3-fold) and mutagenic activities of DEN,
N-nitrosodimethylamine and
N-nitrosopyrrolidine in the presence of rat liver S9 (1.5- to 2.4-fold). This was not the case with
CYP1A1/2, CYP2A1/2,
CYP2B1/2 or CYP3A2, nor with the activities of 2-amino-3-methylimidazo[4,5-f]
quinoline, 3-amino-1-methyl-5H-pyrido[4,3-b]
indole,
aflatoxin B(1) or other N-
nitroso compounds (NOCs), including NMBA.
Ethanol-induced elevations of
CYP2A and
CYP2E1 were observed in the oesophagus (up to 1.7- and 2.3-fold) and kidney (up to 1.5- and 1.8-fold), but not in the lung or colon. In oesophagus and kidney, the mutagenic activities of NMBA and four NOCs were markedly increased (1.3- to 2.4-fold) in treated rats. The application of several CYP inhibitors revealed that
CYP2A were likely to contribute to the enhancing effect of
ethanol on NMBA activation in the rat oesophagus and kidney, but that
CYP2E1 failed to do so. These results showed that the enhancing effect of
ethanol on NMBA-induced oesophageal
carcinogenesis could be attributed to an increase in the metabolic activation of NMBA by oesophageal
CYP2A during the initiation phase, and that this occurred independently of
CYP2E1.