UGT1A1多态性与UGT1A1抑制药物相关药物性肝损伤的关系

doi:10.3969/j.issn.1006-5725.2025.04.019

Abstract

Abstract:

Objective To investigate the association between UGT1A1 inhibitors-induced liver injury （DILI） and UGT1A1 gene polymorphisms through a pharmacogenomics approach. Methods Information on relevant drugs that may induce liver injury， blood routine tests， and liver function tests was collected from hospitalized patients diagnosed with DILI between June 2022 and June 2024. Relevant databases were searched to categorize DILI-associated drugs into UGT1A1 enzyme inhibitors and those without interaction with UGT1A1. Sanger sequencing or MassARRAY SNP typing technology was utilized to detect and genotype the UGT1A1 gene. Results A total of 219 patients with drug-induced liver injury （DILI） were enrolled， including 98 males， with a mean age of 46.32 ± 14.95 years. A literature search of relevant databases revealed that 20 drugs （16.26%， 20/123） associated with DILI had inhibitory effects on the UGT1A1 enzyme. The proportion of DILI cases related to UGT1A1 inhibitors was 60.73% （133/219）. Compared to non-UGT1A1 inhibitor-related DILI group， the UGT1A1 inhibitor-related DILI group exhibited significantly higher levels of ALT， AST， ALP， and GGT （P < 0.05）， while no significant differences were observed in age， gender， TBIL， IBIL， WBC， Hb， PLT， injury type， or injury grade （P > 0.05）. The prevalence of UGT1A1 polymorphisms was significantly higher in the UGT1A1 inhibitor-related DILI group （68.42%） compared to the non-UGT1A1 inhibitor-related DILI group （51.16%）， with an odds ratio （OR） of 2.068 （95% CI： 1.183 to 3.617； χ2 = 6.58， P = 0.010）. There was also a significant difference in the distribution of genotypes between the UGT1A1 inhibitor-related and non-UGT1A1 inhibitor-related DILI groups （χ2 = 9.60， P = 0.022）. Univariate logistic regression analysis indicated that ALT and UGT1A1*6 were associated with UGT1A1 inhibitor-related DILI， while multivariate analysis confirmed that UGT1A1*6 was independently associated with UGT1A1 inhibitor-related DILI ［OR（95%CI） = 3.143 （1.398 to 7.067）， P = 0.006］. Conclusion The UGT1A1*6 allele increases the susceptibility to drug-induced liver injury （DILI） associated with UGT1A1 inhibitory drugs.

Key words: drug-induced liver injury, gene polymorphism, UGT1A1, drug, inhibitor

CLC Number:

R575.1

Yujia LU,Keying OU,Yueyang MA,Chuansu YUAN,Bin LIU,Yongfeng YANG,Qingfang. XIONG. Study on the relationship between UGT1A1 polymorphism and UGT1A1 inhibitory drugs⁃induced liver injury[J]. The Journal of Practical Medicine, 2025, 41(4): 588-593.

Figures/Tables 4

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References 26

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种类	构成比	药物
中草药、中成药	97（44.29）	土三七、何首乌、补骨脂、小柴胡、蒲地蓝、小金片、生发胶囊、前列康等
西药	93（42.47）
抗感染药物		异烟肼；阿莫西林、罗红霉素、阿奇霉素、利托那韦、阿扎那韦等
非甾体类抗炎药		对乙酰氨基酚、氨酚烷胺、氨基水杨酸、塞来昔布等
降血压、降糖、降血脂药物、抗前列腺药物等		苯磺酸氨氯地平片、替格瑞洛、马来酸依那普利、阿托伐他汀钙片、舒瑞伐他汀、甲基硫氧嘧啶、西洛多辛等
抗肿瘤药物		PD-1、PD-L1、索拉非尼等
精神类药物		抗焦虑药物、抗抑郁药物等
其他		减肥药、保健品、油漆、化学品、染发剂等
中西药混合	29（13.24）	阿莫西林+护胃中药汤药、对乙酰氨基酚+小柴胡或蒲地蓝等

UGT1A1酶	药物
抑制剂	甘草、芫花、黄芩、大黄、何首乌、石斛、穿心莲、补骨脂、酮康唑、索拉非尼、拉帕替尼、阿扎那韦、利托那韦、伊立替康
底物+抑制剂	对乙酰氨基酚、双氯芬酸钠
底物	卡马西平、依折麦布、雷洛昔芬、曲伐沙星

项目	非UGT1A1药物组（n = 86）	UGT1A1抑制药物组（n = 133）	t/Z/χ2值	P值
年龄（x ± s）/岁	45.30 ± 14.13	46.98 ± 15.48	-0.81	0.417
男/女/例	44/42	54/79	2.36	0.125
TBIL/（μmol/L）	49.65（18.07， 144.98）	51.75（18.10， 140.25）	-0.49	0.623
IBIL/（μmol/L）	11.60（7.07， 40.12）	9.80（5.27， 22.38）	-1.79	0.074
ALT/（U/L）	109.15（66.93， 322.50）	261.60（101.80， 633.40）	-3.49	< 0.001
AST/（U/L）	83.50（38.50， 231.20）	152.10（60.60， 359.00）	-3.25	0.001
ALP/（U/L）	131.70（90.55， 226.50）	165.00（112.25， 262.00）	-2.04	0.042
GGT/（U/L）	109.00（53.75， 211.50）	179.00（70.20， 340.00）	-2.28	0.023
WBC/（10⁹/L）	5.80（4.55， 7.13）	5.21（4.17， 6.56）	-1.65	0.098
Hb/（g/L）	131.00（116.00， 149.00）	126.50（117.00， 138.00）	-1.46	0.143
Plt/（10⁹/L）	188.00（134.00， 235.00）	192.00（145.75， 233.00）	-0.17	0.867
UGT1A1多态性位点/［例（%）］	44（51.16）	91（68.42）	6.58	0.010
基因分类［无/UGT1A16、UGT1A1*28/UGT1A1*6+UGT1A1**28］/例	42/11/26/7	42/37/41/13	9.60	0.022
损伤类型（肝细胞/胆汁淤积/混合型）/例	27/38/21	58/40/34	4.94	0.084
损伤分级（1/2/3/4）/例	42/10/14/20	63/26/17/27	2.68	0.444

变量	单因素分析		多因素分析
变量	OR（95%CI）	P值	OR（95%CI）	P值
ALT/（U/L）	1.001（1.001 ~ 1.001）	0.029
AST/（U/L）	1.001（1.000 ~ 1.002）	0.102
ALP/（U/L）	1.001（0.999 ~ 1.002）	0.552
GGT/（U/L）	1.001（1.000 ~ 1.002）	0.076
基因分类
无	1.000（Reference）	-	1.000（Reference）	-
UGT1A1*6	3.364（1.515 ~ 7.467）	0.003	3.143（1.398 ~ 7.067）	0.006
UGT1A1*28	1.577（0.822 ~ 3.025）	0.171	1.462（0.748 ~ 2.859）	0.267
UGT1A16+UGT1A1**28	1.857（0.674 ~ 5.117）	0.231	1.840（0.658 ~ 5.141）	0.245

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Study on the relationship between UGT1A1 polymorphism and UGT1A1 inhibitory drugs⁃induced liver injury

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