Persistent perfluorinated organic compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are used in a variety of industrial applications. They are very stable in the environment, distribute...Persistent perfluorinated organic compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are used in a variety of industrial applications. They are very stable in the environment, distribute widely in the global environment and in wild life, and are detected in human sera. Our searches have detected ppt levels of PFOS and PFOA in the surface water of Japan and China; their levels are generally more than ten times higher in city areas. Neither PFOS nor PFOA is removed by the purification process of city water. Both PFOS and PFOA are detected in sera of all the people of Japan and China (about 1000 times as high as those in surface water), and their concentrations are increasing in both countries, especially in China. PFOS and PFOA primarily distribute to the liver and cause the liver toxicity. They also cause developmental toxicity. PFOS which is not genotoxic in a variety of assay system including our in vivo comet assay, induced tumors of the liver, thyroid and mammary gland of rats. PFOA which is weakly carcinogenic is not mutagenic in many studies including our in vivo comet assay.展开更多
While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from t...While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from the three subjects, we discovered that the three subjects possessed the whole CYP2A6 gene deletion (CYP2A6*4C), a novel genetic polymorphism of the CYP2A6 gene. Genetically engineered Salmonella YG7108 cells expressing human CYP2A6 or CYP2E1 together with the NADPH-CYP reductase were established in our laboratory to compare the mutagen-producing capacity of these enzymes for various N-nitrosamines. We found that CYP2E1 was responsible for the metabolic activation of N-nitrosamines with relatively short alkyl chains, whereas CYP2A6 was involved in the metabolic activation of N-nitrosamines possessing relatively bulky alkyl chains such as a tobacco-specific nitrosamine, NNK, which has been known to cause lung tumor in rodents. Thus, to examine a hypothesis that individuals possessing the CYP2A6*4C have the reduced risk of lung cancer due to the lack of the capacity of the metabolic activation of certain carcinogens in tobacco smoke, a case-control study was performed.展开更多
文摘Persistent perfluorinated organic compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are used in a variety of industrial applications. They are very stable in the environment, distribute widely in the global environment and in wild life, and are detected in human sera. Our searches have detected ppt levels of PFOS and PFOA in the surface water of Japan and China; their levels are generally more than ten times higher in city areas. Neither PFOS nor PFOA is removed by the purification process of city water. Both PFOS and PFOA are detected in sera of all the people of Japan and China (about 1000 times as high as those in surface water), and their concentrations are increasing in both countries, especially in China. PFOS and PFOA primarily distribute to the liver and cause the liver toxicity. They also cause developmental toxicity. PFOS which is not genotoxic in a variety of assay system including our in vivo comet assay, induced tumors of the liver, thyroid and mammary gland of rats. PFOA which is weakly carcinogenic is not mutagenic in many studies including our in vivo comet assay.
文摘While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from the three subjects, we discovered that the three subjects possessed the whole CYP2A6 gene deletion (CYP2A6*4C), a novel genetic polymorphism of the CYP2A6 gene. Genetically engineered Salmonella YG7108 cells expressing human CYP2A6 or CYP2E1 together with the NADPH-CYP reductase were established in our laboratory to compare the mutagen-producing capacity of these enzymes for various N-nitrosamines. We found that CYP2E1 was responsible for the metabolic activation of N-nitrosamines with relatively short alkyl chains, whereas CYP2A6 was involved in the metabolic activation of N-nitrosamines possessing relatively bulky alkyl chains such as a tobacco-specific nitrosamine, NNK, which has been known to cause lung tumor in rodents. Thus, to examine a hypothesis that individuals possessing the CYP2A6*4C have the reduced risk of lung cancer due to the lack of the capacity of the metabolic activation of certain carcinogens in tobacco smoke, a case-control study was performed.
