Genetic predisposition to the metabolism of irinotecan (CPT-11) - Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes
Genetic predisposition to the metabolism of irinotecan (CPT-11) - Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes
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DOI：
10.1172/jci915
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发表时间：
1998-02-15
影响因子：
15.9
通讯作者：
Ratain, MJ
中科院分区：
文献类型：
--
作者：
Iyer, L;King, CD;Ratain, MJ
伊立替康(CPT-11)是一种很有前途的抗肿瘤药物，最近被批准用于治疗转移性结直肠癌患者，其活性代谢产物SN-38是由肝尿苷二磷酸葡萄糖醛酸基转移酶(UGTS)作用形成的。伊立替康治疗的主要剂量限制毒性是腹泻，继发于SN-38的胆汁排泄，其程度由SN-38葡萄糖醛酸化作用确定。本研究的目的是鉴定参与SN-38葡萄糖尿醛酸化的UGT的特异性亚型。在体外，从正常大鼠(n=4)和正常人(n=25)的肝微粒体中筛选SN-38的葡萄糖醛酸化作用。在Gunn大鼠(n=3)和Crigler-Najjar I型(CN-I)综合征患者(n=4)中，在人类的体外SN-38葡萄糖醛酸苷形成率中发现了广泛的受试者间差异。Gunn大鼠和CN-I大鼠缺乏SN-38葡萄糖醛酸化活性，提示SN-38葡萄糖醛酸化反应中UGT1亚型处于极点。SN-38与胆红素葡萄糖醛酸化呈显著正相关(r=0.89；P=0.001)，而对硝基酚与SN-38葡萄糖醛酸化相关性较差(r=0.08；P=0.703)。仅在转导UGT1A1同工酶的HK293细胞中观察到完整的SN-38葡萄糖醛酸化，这些结果表明UGT1A1是SN-38葡萄糖醛酸化的异构体，提示伊立替康的代谢具有遗传易感性，提示UGT1A1活性低的患者，如吉尔伯特综合征患者，发生伊立替康毒性的风险增加。
Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer, Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs), The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation, The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation, In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome, A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the pole of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703), Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme, These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation, These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.