Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes
Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes
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DOI：
10.1093/toxsci/kfi211
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发表时间：
2005-09-01
影响因子：
3.8
通讯作者：
Mutlib, A
中科院分区：
文献类型：
--
作者：
Kostrubsky, SE;Sinclair, JF;Mutlib, A
在这里，我们提出了一个临床前模型，以评估药物相互作用，由于抑制葡萄糖醛酸化。抗癫痫药苯巴比妥（PB）或苯妥英（PH）治疗与患者中对乙酰氨基酚（APAP）肝毒性发生率增加相关。在人肝细胞中，我们发现APAP（5 mM）的毒性增加，同时治疗苯巴比妥（2 mM）或苯妥英（0.2 mM）。相反，在APAP治疗前用PB预处理48小时不会增加APAP毒性，除非两种药物同时存在。APAP与PB或PH联合处理的细胞早在1 h就出现蛋白质合成减少，24 h出现超微结构变化，48 h出现肝酶释放。毒性与APAP葡萄糖醛酸化抑制相关。PB或PH还抑制大鼠和人肝微粒体中的APAP葡萄糖醛酸化，并表达人UGT 1A6、1A9和2B15。与完整肝细胞一样，PB和PH既没有羟基化也没有葡萄糖醛酸化，表明UGT的直接抑制。我们的研究结果表明，在多种药物治疗中，UGT和其中一种药物之间的抑制复合物可导致葡萄糖醛酸化降低，并增加联合给药药物的全身暴露和毒性。
Here we present a preclinical model to assess drug-drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.2 mM). In contrast, pretreatment with PB for 48 h prior to APAP treatment did not increase APAP toxicity unless both drugs were present simultaneously. Cells treated with APAP in combination with PB or PH experienced decreases in protein synthesis as early as 1 h, ultrastructural changes by 24 h, and release of liver enzymes by 48 h. Toxicity correlated with inhibition of APAP glucuronidation. PB or PH also inhibited APAP glucuronidation in rat and human liver microsomes and expressed human UGT1A6, 1A9, and 2B15. As with intact hepatocytes, PB and PH were neither hydroxylated nor glucuronidated, suggesting the direct inhibition of UGTs. Our findings suggest that, in multiple drug therapy, an inhibitory complex between UGT and one of the drugs can lead to decreased glucuronidation and increased systemic exposure and toxicity of a coadministered drug.