To elucidate the mechanism underlying suppression by
curcumin of esophageal
carcinogenesis induced by NMBA, we evaluated the CYP level and mutagenic activation of
environmental carcinogens, by immunoblot analyses and Ames preincubation test, respectively, and
bilirubin,
4-nitrophenol and
testosterone UDPGT activities in F344 rats treated with
curcumin and/or NMBA. No significant alterations in the hepatic levels of constitutive CYP
proteins, mutagenic activation by liver S9 or hepatic UDPGT activities were produced by subcutaneous treatment with 0.5 mg/kg NMBA for 5 weeks and/or feeding of 0.05% and 0.2%
curcumin for 6 weeks. In contrast, gavage of 0.2%
curcumin decreased esophageal
CYP2B1 and 2E1 by up to 60%, compared with vehicle control. Similarly, intragastric treatment with 270 mg/kg
curcumin decreased esophageal and gastric
CYP2B1 and
CYP2E1, but not in lung, kidney or intestine. Conversely, large intestinal
CYP2B1 was 2.8-fold higher in the treated rats than in control rats. Mutagenic activities of NOC, including NMBA, in the presence of esophagus and stomach S9 were markedly decreased in the treated rats, whereas those in the presence of large intestine S9 were 2.2-3.0-fold above control. These results show that modifying effects of
curcumin on esophageal
carcinogenesis can be attributed to a decrease in metabolic activation of NMBA by esophageal
CYP2B1 during the initiation phase, without the contribution of metabolic activation and inactivation by liver. Further, the present findings suggest the potential of
curcumin for modification of gastric and intestinal
carcinogenesis initiated with NOC.