イソチオシアネートとクルクミンによるラットにおける乳腺と食道抗発がん作用と代謝活性化

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  • Mechanism underlying chemoprevention by α-naphthyl isothiocyanate or curcumin of mammary or esophageal carcinogenesis in rats
  • イソチオシアネート ト クルクミン ニ ヨル ラット ニ オケル ニュウセン ト ショクドウ コウハツガン サヨウ ト タイシャ カッセイカ

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Hepatic cytochrome P-450 (CYP) 1A1, 51 and 53kDa proteins and constitutive CYP1A2 (3.8-fold) and 2B2 (4.0-fold), but not CYP2B1, 2E1 and 3A2, were induced by i.g. treatment with 85 mg/kg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) eight times over 11 days in female SD rats. Feeding 400 p.p.m. α-naphthyl isothiocyanate (ANIT) in a high fat diet for 3 weeks induced three CYP1A proteins but not CYP1A2; this enhancement was much lower compared to that seen with PhIP. PhIP treatment and subsequent use of liver S9 fraction in S.typhimurium TA98 mutation assay showed 2.8-12.9-fold elevation of mutagenicity by PhIP, four other heterocyclic amines (HCAs) and benzo[a]pyrene (BP), whereas no significant alterations in the TA98 mutagenic activities of these chemicals were produced with S9 prepared after gavage with ANIT. The combination of PhIP and ANIT markedly decreased three liver CYP1A proteins except CYP1A1 and CYP2B2, and the liver S9 from this combination showed reduced mutagenic activities of HCAs and BP. PhIP and ANIT enhanced UDP-glucuronyltransferase (UDPGT) activity towards 4-nitrophenol 2.2- and 1.6- fold, respectively, and the combined administration showed much higher induction (4.7-fold). These results clearly indicate that chemoprevention by ANIT of PhIP-induced rat mammary carcinogenesis can be attributed to a dual action mechanism; a decrease in metabolic activation of PhIP by hepatic CYP1A2 and an increase in the detoxification by UDPGT but not by CYP1A1. On the other hand, no significant alterations in the hepatic levels of these enzymes and activities were produced by s.c. treatment with 0.5 mg/kg N-nitrosomethylbenzylamine (NMBA) three times per week for 5 weeks, feeding of —0.2% curcumin in the diet for 6 weeks, or both, in male F344 rats. In contrast, gavage of curcumin decreased the constitutively detected CYP2B1 and 2E1 in the esophagus, and a single dose of 270 mg/kg curcumin caused 40% decreases (P<0.01) in both CYP species. This suggests that suppression by curcumin of NMBA-induced esophageal carcinogenesis can be attributed to a decrease in esophageal activation of NMBA during the initiation phase, but not attributed to metabolic activation and inactivation via glucuronidation in the liver. Nevertheless, these are the first demonstrations that a HCA can induce hepatic CYP2B2, that an isothiocyanate can suppress metabolic activation by hepatic CYP1A and 2B, and that curcumin shows a suppressive effect on esophagus CYP2B and 2E1.

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