Rickert D E, Long R M, Dyroff M C, Kedderis G L
Chem Biol Interact. 1984 Dec;52(2):131-9. doi: 10.1016/0009-2797(84)90067-x.
The mononitrotoluenes are important industrial chemicals which display isomeric specificity in their ability to induce hepatic DNA excision repair in Fischer-344 rats. Covalent binding of the structurally related hepatocarcinogen, 2,6-dinitrotoluene, to hepatic DNA is markedly decreased by prior administration of the sulfotransferase inhibitors pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP). The objectives of this study were to determine whether hepatic macromolecular covalent binding of the mononitrotoluene isomers differed and to determine whether covalent binding of the mononitrotoluenes to hepatic DNA in vivo was decreased by inhibitors of sulfotransferase. Male Fischer-344 rats were given a single oral dose of [ring-U-14C]-2-, 3- or 4-nitrotoluene (2-, 3- or 4-NT) and killed at various times thereafter. Livers were removed and analyzed for total and covalently bound radiolabel. Maximal concentrations of total radiolabel were observed between 3 and 12 h after the dose, and there were no large differences among the 3 isomers in peak concentrations achieved. Covalent binding to hepatic macromolecules was maximal 12 h after administration for all three isomers. Thereafter, concentrations of covalently bound 2-NT-derived material were always 2-6 times higher than those of 3- or 4-NT-derived material. When DNA was isolated from livers of rats given the mononitrotoluenes 12 h previously, only 2-NT was observed to covalently bind at concentrations above the limits of detection of the assay. The covalent binding of 2-NT, but not that of 3- or 4-NT, to both total hepatic macromolecules and DNA was markedly decreased by prior administration of either PCP or DCNP. Covalent binding to hepatic DNA was decreased by greater than 96%. The results of this study correlate well with studies which have demonstrated that 2-NT, but not 3- or 4-NT, induces DNA excision repair. Furthermore, they suggest that 2-NT, like the hepatocarcinogen 2,6-dinitrotoluene, requires the action of sulfotransferase for its conversion to a species capable of covalently binding to hepatic DNA.
一硝基甲苯是重要的工业化学品，在诱导Fischer - 344大鼠肝脏DNA切除修复的能力上表现出异构体特异性。结构相关的肝癌致癌物2,6 -二硝基甲苯与肝脏DNA的共价结合，在预先给予磺基转移酶抑制剂五氯苯酚（PCP）和2,6 -二氯-4 -硝基苯酚（DCNP）后显著降低。本研究的目的是确定一硝基甲苯异构体的肝脏大分子共价结合是否存在差异，以及体内一硝基甲苯与肝脏DNA的共价结合是否会被磺基转移酶抑制剂降低。给雄性Fischer - 344大鼠单次口服剂量的[环-U - 14C]-2 -、3 -或4 -硝基甲苯（2 -、3 -或4 - NT），并在给药后的不同时间处死。取出肝脏并分析总放射性标记物和共价结合的放射性标记物。给药后3至12小时观察到总放射性标记物的最大浓度，三种异构体达到的峰值浓度之间没有很大差异。所有三种异构体给药后12小时，与肝脏大分子的共价结合达到最大值。此后，共价结合的2 - NT衍生物质的浓度总是比3 -或4 - NT衍生物质的浓度高2至6倍。当从12小时前给予一硝基甲苯的大鼠肝脏中分离DNA时，仅观察到2 - NT以高于测定检测限的浓度共价结合。预先给予PCP或DCNP后，2 - NT与总肝脏大分子和DNA的共价结合均显著降低，但3 -或4 - NT的共价结合未受影响。与肝脏DNA的共价结合降低了96%以上。本研究结果与已证明2 - NT而非3 -或4 - NT诱导DNA切除修复的研究结果密切相关。此外，这些结果表明，2 - NT与肝癌致癌物2,6 -二硝基甲苯一样，需要磺基转移酶的作用才能转化为能够与肝脏DNA共价结合的物质。
