Kadlubar F F, Unruh L E, Flammang T J, Sparks D, Mitchum R K, Mulder G J
Chem Biol Interact. 1981 Jan;33(2-3):129-47. doi: 10.1016/0009-2797(81)90036-3.
The hepatic metabolism of arylamine bladder carcinogens to N-hydroxy arylamine N-glucuronides, their excretion in the urine, and their subsequent acidic hydrolysis to highly carcinogenic and reactive N-hydroxy arylamines have been proposed as essential steps in arylamine-induced urinary bladder carcinogenesis. In this study, alteration of urinary pH, inhibition of metabolic sulfation, and blockage of biliary disposition were shown to profoundly affect the urinary excretion of the probable ultimate bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA) and its N-glucuronide conjugate. The normal pH of rat urine (6.7) was altered to 5.7 or 7.7 by administration of NH4Cl or NaHCO3 in the drinking water. Subsequent treatment with either 2-naphthylamine (2-NA) or 2-nitronaphthalene (2-NN) resulted in increased urinary levels of free N-HO-2-NA (relative to its N-glucuronide) in acidic urines and decreased relative amounts of free N-HO-2-NA in alkaline urines. In addition, 2-NN yielded 5--10-fold greater levels of urinary N-HO-2-NA and its N-glucuronide than rats given 2-NA; and 2-NA was not detected as a urinary metabolite of 2-NN. Some 12 additional metabolites of 2-NA and 2-NN were also found. Of these, 2-amino-1-naphthol and its sulfate and glucuronide conjugates were quantitated. From these data, 2-NA and 2-NN appear to share common metabolic pathways which yield free N-HO-2-NA as a putative ultimate urinary bladder carcinogen. Pentachlorophenol, a known inhibitor of hepatic sulfotransferases, was shown to cause a 2--3-fold increase in the urinary levels of N-HO-2-NA N-glucuronide and N-HO-2-NA from 2-NA-treated rats. Similarly, inhibition of the biliary excretion of 2-NA by bile duct ligation resulted in a 6-fold increase in total urinary N-HO-2-NfA. Furthermore, analyses of bile revealed that substantial amounts of N-HO-2-NA N-glucuronide, but not free N-HO-2-NA, were present. The role of urinary versus biliary excretion of N-hydroxy arylamines in relation to bladder and colon carcinogenesis is discussed.
芳胺膀胱致癌物在肝脏代谢为N - 羟基芳胺N - 葡萄糖醛酸苷，经尿液排泄，随后经酸性水解生成高致癌性和高反应性的N - 羟基芳胺，这些过程被认为是芳胺诱导膀胱癌发生的关键步骤。在本研究中，尿液pH值的改变、代谢性硫酸化的抑制以及胆汁排泄的阻断均被证明会深刻影响可能的最终膀胱致癌物N - 羟基 - 2 - 萘胺（N - HO - 2 - NA）及其N - 葡萄糖醛酸苷结合物的尿液排泄。通过在饮用水中给予氯化铵或碳酸氢钠，将大鼠尿液的正常pH值（6.7）改变为5.7或7.7。随后用2 - 萘胺（2 - NA）或2 - 硝基萘（2 - NN）进行处理，结果显示在酸性尿液中游离N - HO - 2 - NA的尿液水平升高（相对于其N - 葡萄糖醛酸苷），而在碱性尿液中游离N - HO - 2 - NA的相对含量降低。此外，与给予2 - NA的大鼠相比，2 - NN产生的尿液中N - HO - 2 - NA及其N - 葡萄糖醛酸苷水平高出5 - 10倍；并且未检测到2 - NA作为2 - NN的尿液代谢产物。还发现了2 - NA和2 - NN的另外约12种代谢产物。其中，对2 - 氨基 - 1 - 萘酚及其硫酸盐和葡萄糖醛酸苷结合物进行了定量分析。根据这些数据，2 - NA和2 - NN似乎共享共同的代谢途径，生成游离的N - HO - 2 - NA作为假定的最终膀胱致癌物。五氯苯酚是一种已知的肝脏磺基转移酶抑制剂，已证明它会使2 - NA处理的大鼠尿液中N - HO - 2 - NA N - 葡萄糖醛酸苷和N - HO - 2 - NA的水平增加2 - 3倍。同样，胆管结扎抑制2 - NA经胆汁排泄导致尿液中总N - HO - 2 - NfA增加6倍。此外，胆汁分析显示存在大量的N - HO - 2 - NA N - 葡萄糖醛酸苷，但不存在游离的N - HO - 2 - NA。本文讨论了N - 羟基芳胺经尿液与胆汁排泄在膀胱癌和结肠癌发生中的作用。
