HepaticMicrosomalN-Glucuronidationand NucleicAcid Binding of N-HydroxyArylaminesin Relationto Urinary Bladder Carcinogenesis1
HepaticMicrosomalN-Glucuronidationand NucleicAcid Binding of N-HydroxyArylaminesin Relationto Urinary Bladder Carcinogenesis1
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肝微粒体 N-葡萄糖醛酸化和 N-羟基芳胺的核酸结合与膀胱癌发生的关系1
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发表时间：
1977
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通讯作者：
E. Miller
中科院分区：
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作者：
F. Kadlubar;J. Miller;E. Miller
摘要狗、大鼠或人的5‘-二磷酸葡萄糖酸强化的肝微体能迅速代谢[~3H]-N-羟基-2-萘胺(N-HO-2-NA)，经/3-葡萄糖苷酶处理后，可产生98%的母体N-羟基胺。通过对葡萄糖醛酸苷及其硝酮衍生物的紫外、红外和质谱分析，鉴定了该变闪石为N-(f3-i-glucosidunonyl)-N-hydnoxy-2naphthylamine。N-羟基-1-萘胺(N-HO-I-NA)、N-羟基-4-氨基联苯(N-H0-ABP)或2-氨基荧光烯、4-氨基偶氮苯或N-乙酰基-2-氨基荧光烯与5‘-二磷酸葡萄糖单酸强化的肝微球作用也可产生水溶性产物。/3-葡萄糖醛酸酶处理释放了80%~90%的[~3H]-N-HO-I-NA和[~3H]-N-HO-ABP结合物，它们是乙醚可抽提物。N-HO-I-NA、N-HO 2-NA和N-HO-ABP以及这些N-HO-I-NA和N-HO-ABP的葡萄糖醛酸苷在近中性pH下相对稳定且无反应。在pH为5时，N-HO-2-NA的N-葡萄糖醛酸苷和N-HO-I-NA和N-HO ABP的N-葡萄糖醛酸苷被迅速水解成N-羟基氨酰胺，然后再转化为能够与核酸共价结合的活性衍生物。这些数据支持芳胺类膀胱癌致癌物在肝脏中被N-氧化和N-葡萄糖醛酸化，N-葡萄糖苷类化合物被转运到膀胱的概念。在狗和人的正常酸性尿液中，葡萄糖醛酸类化合物被水解成羟基芳胺，后者被转化为高活性的亲电淀粉胺离子，这可能是诱发膀胱癌的关键反应。
SUMMARY Unidine 5'-diphosphoglucumonic acid-fortified hepatic mi crosomes from dogs, rats, or humans rapidly metabolized [3H]-N-hydroxy-2-naphthylamine (N-HO-2-NA) to a water soluble product that yielded 98% of the parent N-hydnoxy amine upon treatment with /3-glucunonidase. The metabo lite was identified as N-(f3-i-glucosidunonyl)-N-hydnoxy-2naphthylamine from ultraviolet, infrared, and mass spectral analyses of the glucuronide and its nitrone derivative. Incu bation of N-hydroxy-1-naphthylamine (N-HO-i-NA), N-hy droxy-4-aminobiphenyl (N-H0-ABP), or the N-hydroxy de mivatives of 2-aminofluomene, 4-aminoazobenzene, or Nacetyl-2-aminofluomene with unidme 5'-diphosphoglucu monicacid-fortified hepatic microsomes also yielded water soluble products. /3-Glucuronidase treatment released 80 to 90% of the [3H]-N-HO-i-NA and [3H]-N-HO-ABPconjugates as tnitiated ether-extractable derivatives. N-HO-i-NA, N-HO 2-NA, and N-HO-ABP and the glucuronides of these Nhydmoxyanylamines were relatively stable and nonreactive near neutral pH. At pH 5, the N-glucumonide of N-HO-2-NA and the presumed N-glucuronides of N-HO-i-NA and N-HO ABP were rapidly hydrolyzed to the N-hydroxy anylamines that were then converted to reactive derivatives capable of binding covalently to nucleic acids. These data support the concept that arylamine bladder carcinogens are N-oxidized and N-glucumonidated in the liver and that the N-glucumonides are transported to the urinary bladder. The hydrolysis of the glucuronides to Nhydroxy arylamines and the conversion of the latter deniva tives to highly reactive electrophilic amylnitrenium ions in the normally acidic urine of dogs and humans may be critical reactions for tumor induction in the urinary bladder.