ORGAN AND SPECIES SPECIFICITIES OF CHEMICAL CARCINOGENS

人类和啮齿动物组织代谢已知或 怀疑是化学致癌物正在调查中。 的 代谢概况和遗传毒性的化学品， 然后将人体组织激活与结果进行比较， 从啮齿类动物组织中提取，以帮助推断啮齿类动物中的作用 对人类的潜在影响。 人类和啮齿动物肝脏， 肾脏细胞代谢的致癌模型芳香族化合物 胺，乙酰氨基芴，已经完成。 人类 肝脏，9个单独的组织标本进行了研究， 在所有情况下观察到的羟基化产物的复杂模式 例 同样的羟基化产物也被观察到， 大鼠肝细胞;然而，9份人类样本中有8份 比大鼠肝细胞更活跃的代谢者。 的 人体整体代谢的个体间差异是 约4倍;尽管单个代谢物的变化 高达35倍。 人肝细胞结合的能力 这些与硫酸盐或葡萄糖醛酸的羟基化产物被 也高于大鼠肝细胞和人类个体间 对缀合物的变异为约8倍。 人肝细胞 在产生代谢物方面也比大鼠肝细胞更活跃 对鼠伤寒沙门氏菌有致突变性。 外贸 肾脏组织也表明，人体细胞 比老鼠肾脏组织更活跃的人类细胞 比大鼠肾细胞更活跃， 和致突变的乙酰氨基芴代谢物;但肾细胞 这两个物种的活性都低于肝细胞。 再次，关于 人类肾脏代谢的个体间差异为4倍， 观察 这些研究的结果现在正在扩大到 其他NTP化学品，以确定这些数据是否用于 结合药效学和遗传毒性数据， 有助于从啮齿动物推断到人类。

The ability of human and rodent tissues to metabolize known or suspected chemical carcinogens is being investigated. The metabolic profile and genetic toxicity of the chemicals with human tissue activation are then being compared to the results from rodent tissues to aid the extrapolation of effects in rodents to potential effects in humans. Human and rodent liver and kidney cell metabolism of the model carcinogenic aromatic amine, acetylaminofluorene, has been completed. For human liver, nine individual tissue specimens have been investigated and a complex pattern of hydroxylated products observed with all cases. The same hydroxylated products were also observed with rat hepatocytes; however eight of the nine human samples were more active metabolizers than the rat hepatocytes. The interindividual variation in the overall human metabolism was about 4-fold; although variation in individual metabolites was as high as 35-fold. The ability of human hepatocytes to conjugate these hydroxylated products with sulfate or glucuronic acid was also greater than in rat hepatocytes and the human interindividual variation to conjugate was about 8-fold. Human hepatocytes were also more active that rat hepatocytes in producing metabolites which were mutagenic to Salmonella typhimurium. Studies with kidney tissues have also indicated that human cells are more active than rat kidney tissues have also indicated that human cells are more active that rat kidney cells in producing hydroxylated and mutagenic acetylaminofluorene metabolites; but kidney cells from both species are less active than hepatocytes. Again, about a 4-fold interindividual variation in human kidney metabolism was observed. The results of these studies are now being extended to other NTP chemicals to determine if these data when used in combination with pharmacodynamic and genetic toxicity data can aid in rodent to human extrapolation.