Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites - pH stability and synthesis by human and dog liver
Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites - pH stability and synthesis by human and dog liver
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DOI：
10.1016/0006-2952(96)00165-7
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发表时间：
1996-06-28
影响因子：
5.8
通讯作者：
Davis, BB
中科院分区：
文献类型：
--
作者：
Babu, SR;Lakshmi, VM;Davis, BB
芳胺的葡萄糖醛酸化物结合物被认为在致癌过程中起着重要作用。本文研究了4-氨基联苯及其N-羟基代谢物在人和狗肝脏中的pH稳定性及其葡醛酸偶联物的合成。狗和人肝切片与0.06 mM[H-3]-4-氨基联苯孵育后，主要产物为N-葡萄糖醛酸基对氨基联苯。孵育2小时后，犬和人体内4-氨基联苯的N-葡萄糖醛酸苷分别占总放射性的52%和27%。当4-氨基联苯、N-羟基-4-氨基联苯或N-羟基-N-乙酰基-4-氨基联苯加入到含有[C-14]UDP-葡萄糖醛酸的人微粒体中时，在高效液相中检测到一个新的产物峰。在0.5 mm处，葡萄糖醛酸化反应的速率为N-羟基-N-乙酰基-4-氨基联苯。4-氨基联苯生成N-葡萄糖醛酸苷的速率与联苯胺和N-乙酰基联苯胺的生成速率相似。4-氨基联苯和N-羟基-4-氨基联苯的葡萄糖醛酸苷在pH为5.5时均不稳定，其T-1/2值分别为10.5和32min。N-羟基-N-乙酰基-4-氨基联苯的葡萄糖醛酸苷在pH分别为5.5和7.4时，在55分钟和68分钟时不耐酸，其T-1/2值分别为5.5和7.4。4-氨基联苯的葡萄糖醛酸苷是最不稳定的酸结合物。因此，4-氨基联苯葡萄糖醛酸苷是狗和人肝脏切片代谢的主要产物，可能在致癌过程中发挥重要作用。
Glucuronide conjugates of arylamines are thought to be important in the carcinogenic process. This study investigated the pH stability and synthesis of glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites by human and dog liver. Both dog and human liver slices incubated with 0.06 mM [H-3]-4-aminobiphenyl produced the N-glucuronide of 4-aminobiphenyl as the major product. Alter 2 hr of incubation, the N-glucuronide of 4-aminobiphenyl represented 52 and 27% of the total radioactivity recovered by HPLC in dog and human, respectively. When 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, or N-hydroxy-N-acetyl-4-aminobiphenyl was added to human microsomes containing [C-14]UDP-glucuronic acid, a new product peak was detected by HPLC. At 0.5 mM, the rate of glucuronidation was N-hydroxy-N-acetyl-4-aminobiphenyl > N-hydroxy-4-aminobiphenyl > 4-aminobiphenyl. The rate of formation of the N-glucuronide of 4-aminobiphenyl was similar to that observed with benzidine and N-acetylbenzidine. The glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl were both acid labile with T-1/2 values of 10.5 and 32 min, respectively, at pH 5.5. The glucuronide of N-hydroxy-N-acetyl-4-aminobiphenyl was not acid labile with T-1/2 values at pH 5.5 and 7.4 of 55 and 68 min, respectively. The glucuronide of 4-aminobiphenyl was the most acid labile conjugate examined. Thus, the glucuronide oi 4-aminobiphenyl is a major product of dog and human liver slice metabolism and likely to play an important role in the carcinogenic process.