Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway
Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway
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DOI：
10.1016/j.taap.2008.07.020
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发表时间：
2008-11-01
影响因子：
3.8
通讯作者：
O'Brien, Peter J.
中科院分区：
文献类型：
--
作者：
Char, Tom S.;Wilson, John X.;O'Brien, Peter J.
工业产生的有机氯是持久性环境污染物，是一个持续存在的健康问题。这些化合物对药物代谢的影响尚不清楚。在当前的研究中，我们提供的证据表明，微量有机氯对对乙酰氨基酚 (APAP) 葡萄糖醛酸化的抑制与其刺激 D-葡萄糖醛酸途径导致抗坏血酸合成的能力密切相关。评估了一组 6 种芳基化有机氯，包括 5 种 PCB（多氯联苯）同系物，对雄性 Sprague-Dawley 大鼠分离肝细胞中 APAP 葡萄糖醛酸化的影响。发现每种有机氯抑制 APAP 葡萄糖醛酸化的能力与其刺激抗坏血酸合成的能力成正比。 PCB153、PCB28 和双-(4-氯苯砜) (BCPS) 按升序排列是抑制 APAP 葡萄糖醛酸化和刺激 D-葡萄糖醛酸途径最有效的有机氯。 3种APAP葡萄糖醛酸化抑制剂均不能改变UGT1A6、UGT1A7和UGT1A8（大鼠中负责APAP葡萄糖醛酸化的主要亚型）的表达，然而，它们抑制APAP葡萄糖醛酸化的功效与其消耗UDP-葡萄糖醛酸（UDPGA）的能力成正比。 BCPS 介导的对分离肝细胞中 APAP 葡萄糖醛酸化的抑制具有非竞争性特征，并且对细胞色素 P450 的失活不敏感。有效的有机氯还能够选择性地刺激分离的微粒体中UDPGA水解为UDP和葡萄糖醛酸，但当UDPGA过量时不能抑制微粒体中的APAP葡萄糖醛酸化。我们得出的结论是，有机氯能够通过将 UDPGA 重定向至 D-葡萄糖醛酸途径来消耗 UDPGA，从而抑制肝细胞中的 APAP 葡萄糖醛酸化。由于抑制是非竞争性的，低浓度的这些化合物可能对肝细胞的葡萄糖醛酸化能力具有长期抑制作用。 (C) 2008 Elsevier Inc. 保留所有权利。
Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the D-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the D-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional to their capacity to deplete UDP-glucuronic acid (UDPGA). BCPS-mediated inhibition of APAP glucuronidation in isolated hepatocytes had non-competitive characteristics and was insensitive to the inactivation of cytochrome P450. The effective organochlorines were also able to selectively stimulate the hydrolysis of UDPGA to UDP and glucuronate in isolated microsomes, but could not inhibit APAP glucuronidation in microsomes when UDPGA was in excess. We conclude that organochlorines are able to inhibit APAP glucuronidation in hepatocytes by depleting UDPGA via redirecting UDPGA towards the D-glucuronate pathway. Because the inhibition is non-competitive, low concentrations of these compounds could have long term inhibitory effects on the glucuronidating capacity of hepatocytes. (C) 2008 Elsevier Inc. All rights reserved.