Modification by curcumin of mutagenic activation of carcinogenic N-nitrosamines by extrahepatic cytochromes P-450 2B1 and 2E1 in rats.
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.
Mori
Yukio
Y
Institute of Biological Pharmacy, Gifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, Japan. ymori@gifu-pu.ac.jp
Tatematsu
Kenjiro
K
Koide
Akihiro
A
Sugie
Shigeyuki
S
Tanaka
Takuji
T
Mori
Hideki
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives / Q000378:metabolism; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009596:Nitrophenols / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000187:drug effects / Q000201:enzymology; D013739:Testosterone / Q000378:metabolism; D000090264:UDP-Glucuronosyltransferase 1A9
D000970:Antineoplastic Agents; D002273:Carcinogens; D009596:Nitrophenols; D009602:Nitrosamines; D013739:Testosterone; C014707:nitrosobenzylmethylamine; D019392:Cytochrome P-450 CYP2E1; D019362:Cytochrome P-450 CYP2B1; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D003474:Curcumin; D004128:Dimethylnitrosamine; D001663:Bilirubin; C024836:4-nitrophenol