Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer
Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer
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DOI：
10.1111/j.1349-7006.2006.00321.x
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发表时间：
2006-11-01
期刊：
影响因子：
5.7
通讯作者：
Sasaki, Yasutsuna
中科院分区：
文献类型：
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作者：
Araki, Kazuhiro;Fujita, Ken-Ichi;Sasaki, Yasutsuna
UDP-葡萄糖醛酸基转移酶（UGT）1A 1 *28（UGT 1A 1基因的启动子变体）的药物遗传学检测目前正在临床上进行，以估计伊立替康相关毒性的风险。我们研究了UGT 1A 1 *6和UGT 1A 1 *27的临床意义，这两个变异体位于UGT 1A 1基因的外显子1，主要见于亚洲人。研究组包括46名接受各种化疗方案的日本患者，包括剂量为50 - 180 mg/m2的伊立替康（2）。探索了UGT 1A 1基因型与伊立替康活性代谢产物（SN-38）与SN-38葡糖苷酸（SN-38 G）的血浆浓度-时间曲线下面积（AUC）比值（用作UGT 1A 1活性的替代物（AUC（SN-38）/AUC（SN-38 G））之间的药物遗传学关系。无患者为UGT 1A 1 *28纯合子，无患者为UGT 1A 1 *27纯合子。2例为UGT 1A 1 *28杂合子。2例为UGT 1A 1 *6纯合子，15例为UGT 1A 1 *6杂合子，所有患者均为UGT 1A 1 *28野生型。2例患者同时为UGT 1A 1 *28和UGT 1A 1 *6杂合子，存在于不同染色体上。其他25名患者没有研究的变体。同时为UGT 1A 1 *28和UGT 1A 1 *6杂合子的2例患者和UGT 1A 1 *6纯合子的2例患者的AUC（SN-38）/AUC（SN-38 G）比值显著高于其他患者（P = 0.0039）。UGT 1A 1 *28和UGT 1A 1 *6的同时存在，即使是杂合子，也会显著改变伊立替康的分布，可能增加对毒性的敏感性。还应仔细监测UGT 1A 1 *6纯合子患者。除了检测UGT 1A 1 *28外，还应对UGT 1A 1基因编码区的UGT 1A 1多态性进行基因分型，以更准确地预测伊立替康相关毒性，至少在亚洲患者中是如此。
Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.