In Vitro Metabolism of 2-Acetylbenzothiophene: Relevance to Zileuton Hepatotoxicity

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• 作者：Elizabeth M. Joshi ; Brian H. Heasley ; Mahendra D. Chordia ; and Timothy L. Macdonald
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：February 2004
• 年：2004
• 卷：17
• 期：2
• 页码：137 - 143
• 全文大小：137K
• 年卷期：v.17,no.2(February 2004)
• ISSN：1520-5010

文摘

Zileuton, an inhibitor of 5-lipooxygenase, the initial enzyme in the leukotriene pathway,was marketed as a new treatment for asthma. This drug has been associated with liver toxicity,which has limited its clinical usefulness. We provide evidence here that the liver toxicity likelyinvolves a sequence of biotransformations leading to 2-acetylbenzothiophene (2-ABT), whichis subsequently metabolized to give a reactive intermediate(s). In vitro experiments with thehuman lymphoblast MCL5 cell line demonstrated that 2-ABT is cytotoxic in a P450-dependentmanner. Human liver microsome (HLM) incubations with 2-ABT revealed the formation oftwo short-lived oxidized species, "M + 16" and "M + 32". Both of these metabolites formedadducts in the presence of GSH or NAC. Singly oxidized M + 16 adducts, from either GSH orNAC, appeared to be unstable in acidic medium and eliminated water readily to form a newcompound. Authentic synthetic standards demonstrated that 2-ABT-S-oxide M1 correspondedto the M + 16 metabolite and that the S-oxide underwent nucleophilic addition with GSH andNAC to produce the singly oxidized adducts observed in HLM. The S-oxide adducts readilyeliminated water to form a rearomatized 2-ABT-GSH adduct or 2-ABT-NAC adduct. Coelutionexperiments with the synthetic standard confirmed the structure of the eliminated 2-ABT-NAC adduct C1. LC/MS analyses of urine samples collected from rats dosed with zileutonindicate that C1 is a metabolite of zileuton formed in vivo. The in vitro and in vivo datapresented here demonstrate the formation of 2-ABT from zileuton and its further bioactivationto a potentially toxic metabolite.