Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9.

Chemical Research in Toxicology
Peter M RademacherSidney D Nelson

Abstract

The uricosuric diuretic agent tienilic acid (TA) is a thiophene-containing compound that is metabolized by P450 2C9 to 5-OH-TA. A reactive metabolite of TA also forms a covalent adduct to P450 2C9 that inactivates the enzyme and initiates immune-mediated hepatic injury in humans, purportedly through a thiophene-S-oxide intermediate. The 3-thenoyl regioisomer of TA, tienilic acid isomer (TAI), is chemically very similar and is reported to be oxidized by P450 2C9 to a thiophene-S-oxide, yet it is not a mechanism-based inactivator (MBI) of P450 2C9 and is reported to be an intrinsic hepatotoxin in rats. The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P450 2C9-mediated oxidation. In addition, in silico approaches were used to better understand both the mechanisms of oxidation of TA and TAI and/or the structural rearrangements of oxidized thiophene compounds. Incubation of TA with P450 2C9 and NADPH yielded the well-characterized 5-OH-TA metabolite as the major product. However, contrary to previous reports, it was found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of prod...Continue Reading

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Citations

Feb 18, 2016·Pathophysiology : the Official Journal of the International Society for Pathophysiology·Khaled G Abdel-WahhabFathia A Mannaa
Nov 18, 2015·Chemical Research in Toxicology·Chaitanya K JaladankiPrasad V Bharatam
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Sep 19, 2016·Chemosphere·Adrian ImamiHolger Zorn
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Mar 5, 2019·Metabolomics : Official Journal of the Metabolomic Society·Adam M KingRobert Trengove
Mar 4, 2021·The Journal of Organic Chemistry·Jia LiRichard N Zare
Mar 27, 2021·Chemical Research in Toxicology·M Saeed MirzaeiSaber Mirzaei
Apr 27, 2021·Chemical Research in Toxicology·Chaitanya K JaladankiPrasad V Bharatam
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Jul 12, 2014·Chemical Research in Toxicology·Darja GramecMarija Sollner Dolenc

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