Norharmanのco-mutagenic作用機構に関する研究

抄録

Norharman, widely distributed in our environment including cigarette smoke and cooked foods, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of aromatic amines, such as aniline and o-toluidine. Regarding mechanisms of the co-mutagenic action of norharman with aniline, a mutagenic compound, aminophenylnorharman (APNH) is produced by their interaction, and converted to the hydroxyamino derivative which eventually forms the DNA adduct, dG-C8-APNH, and this induces mutations. Other aminophenyl-β-carboline compounds, such as amino-3’-methylphenylnorharman (3’-AMPNH), amino-2’-methylphenylnorharman (2’-AMPNH), aminophenylharman (APH) and amino-3’-methylphenylharman (AMPH), have also been found on reaction of norharman or harman with aniline or toluidine isomers. These compounds showed mutagenic and clastogenic actions in bacterial and mammalian cells. Among them, APNH demonstrated the most potent activity, and it was most extensively studied. When APNH was fed at 10—50 ppm in the diet for 4 weeks to F344 rats, the numbers and areas of liver preneoplastic lesions, GST-P positive foci, were significant. This suggests that APNH would induce liver tumors in rats. Since, APNH was detected in 24 hr urine of rats simultaneously administered with norharman and aniline by gavage, it is likely also to be produced from norharman and aniline in the human body. Therefore, it is conceivable that APNH is a new type of endogenously formed mutagen/carcinogen, involved in human carcinogenesis.