Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases

被引：12

作者：

Yang, Lan ^{[1
]}

Xin, Lihua ^{[1
]}

Shi, Junzu ^{[1
]}

Li, Wei ^{[1
]}

Tian, Min ^{[1
]}

Hu, Zixia ^{[1
]}

Peng, Ying ^{[1
]}

Zheng, Jiang ^{[1
,2
,3
]}

机构：

[1] Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Liaoning, Peoples R China

[2] Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Key Lab Pharmaceut Guizhou Prov, Guiyang 550025, Guizhou, Peoples R China

[3] Guizhou Med Univ, Key Lab Environm Pollut Monitoring & Dis Control, Minist Educ, Guiyang 550025, Guizhou, Peoples R China

来源：

CHEMICAL RESEARCH IN TOXICOLOGY | 2021年 / 34卷 / 06期

基金：

中国国家自然科学基金;

关键词：

BIOACTIVATION; FAILURE;

D O I：

10.1021/acs.chemrestox.1c00060

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Labetalol hydrochloride (LHCl), an alpha- and beta-adrenoreceptor blocker, is widely used for the treatment of hypertension as well as angina pectoris. Previous reports have demonstrated the adverse events during clinical application of LHCl, such as liver injury and acute renal failure. The present study aimed to investigate metabolic activation of LHCl to initiate the elucidation of the mechanisms of its liver toxicity. One glutathione (GSH) conjugate was detected in rat and human primary hepatocytes as well as bile of rats after exposure to LHCl. The GSH conjugate was chemically synthesized and characterized by Q-TOF and H-1 NMR. Pretreatment of 2,6-dichloro-4-nitrophenol (DCNP), a broad-spectrum sulfotransferase (SULT) inhibitor, significantly attenuated the formation of the GSH conjugate in LHCl-treated hepatocytes and animals, indicating the participation of SULTs in metabolic activation of LHCl. Moreover, pretreatment with DCNP displayed significant protection against the observed cytotoxicity in rat primary hepatocytes, which suggests a correlation of the bioactivation of LHCl mediated by SULTs with LHCl-induced hepatotoxicity.

引用

页码：1612 / 1618

页数：7

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