The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
In Vitro Metabolism of 2-Acetylbenzothiophene: Relevance to Zileuton Hepatotoxicity
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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“The exact mechanism of toxicity of zileuton is unknown, but it likely involves production of intermediate reactive metabolites due to oxidative metabolism by the cytochrome P450 isoenzymes 1A2, 2C9, and 3A445.”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [45]
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Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology
Ewart, L., Apostolou, A., Briggs, S. A., Carman, C. V., Chaff, J. T., Heng, A. R., Jadalannagari, S., Janardhanan, J., Jang, K.-J., Joshipura, S. R., et al. (2022) · Communications Medicine · doi:10.1038/s43856-022-00209-1 · Cited by 337
Role of Metabolism in Drug-Induced Idiosyncratic Hepatotoxicity
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Bioactivation Potential of Thiophene-Containing Drugs
Skledar, D. G., Mašič, L. P., & Dolenc, M. S. (2014) · Chemical Research in Toxicology · doi:10.1021/tx500134g · Cited by 255
Minimising the potential for metabolic activation in drug discovery
Kalgutkar, A. S. S., & Soglia, J. R. (2005) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.1.1.91 · Cited by 233
Developing Structure−Activity Relationships for the Prediction of Hepatotoxicity
Greene, N., Fisk, L., Naven, R. T., Note, R., Patel, M. L., & Pelletier, D. J. (2010) · Chemical Research in Toxicology · doi:10.1021/tx1000865 · Cited by 175
Metadata
- Authors
- Joshi, E. M., Heasley, B. H., Chordia, M. D., & Macdonald, T. L.
- Affiliations
- University of Virginia (US)
- 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
- 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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