Lynn R K, Garvie-Gould C T, Milam D F, Scott K F, Eastman C L, Ilias A M, Rodgers R M
Toxicol Appl Pharmacol. 1984 Jan;72(1):1-14. doi: 10.1016/0041-008x(84)90244-8.
The mutagenic and carcinogenic aromatic amine, benzidine (BZ), underwent extensive biotransformation in the rat. Three days after po (5.0 mg/kg) or iv (2.5 mg/kg administration of [14C]BZ, 90% of the radiolabel had been excreted in the urine (25%) and feces (65%); 7% was recovered in the animal. As the dose was increased from 0.5 to 50 mg/kg, the percentage of the dose excreted in urine increased twofold. In distribution studies, a major portion of the iv dose accumulated in the intestinal tract due to the excretion of 71% of the administered radiolabel in bile. The liver, which is a primary target organ of BZ carcinogenicity in rats, contained a higher concentration of radiolabel than other tissues studied. A minimum of 17 urinary and/or biliary metabolites were separated by HPLC. The major metabolites were N-acetyl-BZ(ABZ), N,N'-diacetyl-BZ(DABZ), BZ-N-glucuronide, ABZ-glucuronide, N-OH-DABZ glucuronide, 3-OH-DABZ glucuronide, and a glutathione conjugate of DABZ (3-GSH-DABZ). At low doses (0.5 to 5 mg/kg), 3-OH-DABZ glucuronide, 3-GSH-DABZ, and DABZ were the major urinary or biliary metabolites. However, at higher doses (50 mg/kg), N-OH-DABZ glucuronide, which was a minor metabolite at low doses, became a major urinary and biliary metabolite. Several urinary and biliary metabolites displayed significant mutagenicity in the Salmonella typhimurium (strain TA98)-liver S9-beta-glucuronidase assay. However, N-OH-DABZ glucuronide exhibited a mutagenic potency 10X greater than the other urinary metabolites. Results of these studies demonstrate that BZ is rapidly metabolized via N-acetylation, N-hydroxylation, and aromatic hydroxylation to a variety of mutagenic metabolites which are excreted in urine or bile primarily as glucuronide and/or glutathione conjugates. The most potent mutagen studied was also a major urinary and biliary metabolite.
诱变和致癌芳香胺联苯胺（BZ）在大鼠体内经历了广泛的生物转化。经口给予[14C]BZ（5.0mg/kg）或静脉注射（2.5mg/kg）三天后，90%的放射性标记物已通过尿液（25%）和粪便（65%）排出；7%在动物体内回收。随着剂量从0.5mg/kg增加到50mg/kg，尿液中排出的剂量百分比增加了两倍。在分布研究中，由于71%的给药放射性标记物经胆汁排泄，静脉注射剂量的大部分积聚在肠道中。肝脏是大鼠中BZ致癌作用的主要靶器官，其放射性标记物浓度高于所研究的其他组织。通过高效液相色谱法至少分离出17种尿液和/或胆汁代谢物。主要代谢物为N-乙酰基-BZ（ABZ）、N，N'-二乙酰基-BZ（DABZ）、BZ-N-葡萄糖醛酸苷、ABZ-葡萄糖醛酸苷、N-羟基-DABZ葡萄糖醛酸苷、3-羟基-DABZ葡萄糖醛酸苷以及DABZ的谷胱甘肽结合物（3-GSH-DABZ）。在低剂量（0.5至5mg/kg）时，3-羟基-DABZ葡萄糖醛酸苷、3-GSH-DABZ和DABZ是主要的尿液或胆汁代谢物。然而，在高剂量（50mg/kg）时，低剂量时为次要代谢物的N-羟基-DABZ葡萄糖醛酸苷成为主要的尿液和胆汁代谢物。几种尿液和胆汁代谢物在鼠伤寒沙门氏菌（TA98菌株）-肝脏S9-β-葡萄糖醛酸苷酶试验中显示出显著的诱变性。然而，N-羟基-DABZ葡萄糖醛酸苷的诱变效力比其他尿液代谢物高10倍。这些研究结果表明，BZ通过N-乙酰化、N-羟基化和芳香族羟基化迅速代谢为多种诱变代谢物，这些代谢物主要以葡萄糖醛酸苷和/或谷胱甘肽结合物的形式经尿液或胆汁排出。所研究的最具诱变性的代谢物也是主要的尿液和胆汁代谢物。
