Iyer L, King C D, Whitington P F, Green M D, Roy S K, Tephly T R, Coffman B L, Ratain M J
Committee on Clinical Pharmacology, The University of Chicago, Chicago, Illinois 60637, USA.
J Clin Invest. 1998 Feb 15;101(4):847-54. doi: 10.1172/JCI915.
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 role 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.
伊立替康（CPT - 11）是一种很有前景的抗肿瘤药物，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可被肝脏尿苷二磷酸葡萄糖醛酸转移酶（UGTs）进行葡萄糖醛酸化。伊立替康治疗的主要剂量限制性毒性是腹泻，据信这是由于SN - 38经胆汁排泄所致，其排泄程度由SN - 38葡萄糖醛酸化决定。本研究的目的是确定参与SN - 38葡萄糖醛酸化的UGT的具体同工型。在正常大鼠（n = 4）、正常人（n = 25）、冈恩大鼠（n = 3）和患有Ⅰ型克里格勒 - 纳贾尔综合征（CN - Ⅰ）的患者（n = 4）的肝微粒体中筛选了SN - 38的体外葡萄糖醛酸化情况。在人类中发现体外SN - 38葡萄糖醛酸苷形成速率存在很大的个体间差异。冈恩大鼠和CN - Ⅰ患者缺乏SN - 38葡萄糖醛酸化活性，表明UGT1同工型在SN - 38葡萄糖醛酸化中起作用。观察到SN - 38与胆红素葡萄糖醛酸化之间存在显著相关性（r = 0.89；P = 0.001），而对硝基苯酚与SN - 38葡萄糖醛酸化之间的关系较差（r = 0.08；P = 0.703）。仅在转染了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是负责SN - 38葡萄糖醛酸化的同工型。这些发现表明伊立替康代谢存在遗传易感性，提示UGT1A1活性低的患者，如患有吉尔伯特综合征的患者，可能发生伊立替康毒性的风险增加。
