Modification by curcumin of mutagenic activation of carcinogenic N‐nitrosamines by extrahepatic cytochromes P‐450 2B1 and 2E1 in rats

Abstract

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. (Cancer Sci 2006; 97: 896-904) H uman esophageal cancer has been closely associated with exposure to nitrate and nitrite, which are precursors of NOC, and exposure to NMBA is also associated with an increased risk of human cancer in the esophagus in China. (1)(2)(3)(4) In fact, NMBA is known to be the most potent carcinogen for rat esophagus, irrespective of its mode of administration. (5,6 ) It has been shown that esophageal mucosa microsomes from male Sprague-Dawley rats can form benzaldehyde and formaldehyde from NMBA at rates 1/5 and 1/60 of hepatic levels of both metabolites, respectively, and the metabolisms are inhibited more than 95% by CO and 70% by SKF525A, typical CYP inhibitors.(7) O 6 -methylated guanine level in rats given NMBA is six times higher in esophagus DNA than in liver DNA, (8) and isothiocyanates markedly decrease the incidence and multiplicity of NMBA-induced esophageal tumors, with inhibition of esophageal DNA methylation in F344 rats.(9) Further, it has been shown that ethanol has an enhancing effect on DEN-induced esophageal tumorigenesis in F344 rats, (10) with enhancement of metabolic activation of DEN by hepatic CYP2E1.(11) These findings indicate the importance of metabolic activation of NMBA by the target organ and/or liver during the initiation phase, and some NOC are known to be metabolized in the esophagus at a relatively high rate, often leading to high levels of esophageal D...

Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products

“…In in vivo studies repetitive administration of curcumin to rats resulted in down-regulation of intestinal CYP3A-enzymes, whereas hepatic and renal CYP3A-levels were significantly induced (Zhang et al, 2006). Also, down-regulation of esophagal CYP2B1 and CYP2E1 was reported after intragastric treatment of rats, which might partially explain the chemopreventive activity of curcumin against carcinogenic N-nitrosamines (Mori et al, 2006).…”

Anti cancer effects of curcumin: cycle of life and death

“…Curcumin inhibits of phase I enzymes systems consist of cytochrome P450 isoforms, the P450 reductase, the cytochrome b5 and the epoxide hydrolase and protect from the toxic effects of chemicals and carcinogens [ 60 ]. On the other hand curcumin induces phase II enzymes (glutathione S-transferases and epoxide hydrolase), which play a protective role by eliminating toxic substances and oxidants and conferring benefit in the prevention of the early stages of carcinogenesis [ 98 ].…”

Genotoxicity of a Low-Dose Nitrosamine Mixture as Drinking Water Disinfection Byproducts in NIH3T3 Cells

“…Furthermore, the genotoxic assessments of NAms are usually assessed as mg/L, which is 40-50 million times the concentrations present in drinking water. For example, NDMA has been studied using an Ames assay at 20 m M 35 and with a comet assay at 2.39 m M 36 . Previous genotoxicity studies with NAms-DBPs did not assess the genotoxicity thoroughly with different end points 35 , 36 .…”