Cited by 87Drug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug MetabolismBioactive Compounds and Antitumor Agents

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

Joshi, Elizabeth M., Heasley, Brian H., Chordia, Mahendra D., Macdonald, Timothy L.·2004·Chemical Research in Toxicology

DOI 10.1021/tx0341409

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Abstract

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 likely involves a sequence of biotransformations leading to 2-acetylbenzothiophene (2-ABT), which is subsequently metabolized to give a reactive intermediate(s). In vitro experiments with the human lymphoblast MCL5 cell line demonstrated that 2-ABT is cytotoxic in a P450-dependent manner. Human liver microsome (HLM) incubations with 2-ABT revealed the formation of two short-lived oxidized species, "M + 16" and "M + 32". Both of these metabolites formed adducts in the presence of GSH or NAC. Singly oxidized M + 16 adducts, from either GSH or NAC, appeared to be unstable in acidic medium and eliminated water readily to form a new compound. Authentic synthetic standards demonstrated that 2-ABT-S-oxide M1 corresponded to the M + 16 metabolite and that the S-oxide underwent nucleophilic addition with GSH and NAC to produce the singly oxidized adducts observed in HLM. The S-oxide adducts readily eliminated water to form a rearomatized 2-ABT-GSH adduct or 2-ABT-NAC adduct. Coelution experiments 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 zileuton indicate that C1 is a metabolite of zileuton formed in vivo. The in vitro and in vivo data presented here demonstrate the formation of 2-ABT from zileuton and its further bioactivation to a potentially toxic metabolite.

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Authors: Joshi, E. M., Heasley, B. H., Chordia, M. D., & Macdonald, T. L.
Affiliations: University of Virginia (US)
ORCID: Joshi, Elizabeth M.
Chordia, Mahendra D.
Venue: Chemical Research in Toxicology
Publisher: American Chemical Society (ACS)
Published: 2004-01-24
Volume: 17
Issue: 2
Pages: 137-143
ISSN: 0893-228X (ISSN-L)
1520-5010
DOI: 10.1021/tx0341409
OpenAlex: W2015415371
Cited by: 85
References: 6
Citations by year: 2026: 2 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 7 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 3 · 2012: 8
FWCI: 3.07
Type: journal article
Language: en
Open access: closed
Locations: Chemical Research in Toxicology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords: zileuton, hepatotoxicity, drug metabolism, 5-lipoxygenase inhibitors, leukotriene pathway, S-oxides, glutathione adducts, N-acetylcysteine, reactive metabolites, metabolic activation, human liver microsomes, cytotoxicity
MeSH terms: Animals, Cell Line, Glutathione, Half-Life, Humans, Hydroxyurea, Liver, Magnetic Resonance Spectroscopy, Thiophenes, Spectrometry, Mass, Electrospray Ionization, Rats

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

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