Oxidative activation of the thiophene ring by hepatic enzymes: Hydroxylation and formation of electrophilic metabolites during metabolism of tienilic acid and its isomer by rat liver microsomes
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Cited by (57)
Safety evaluation of substituted thiophenes used as flavoring ingredients
2017, Food and Chemical ToxicologyCitation Excerpt :Ring epoxidation and S-oxidation are the known primary pathways for biotransformation of thiophene derivatives, and the relative contribution of each pathway is a function of the thiophene substructure. GSH conjugation of the reactive intermediate seems to be a key element in inhibiting covalent binding by acting as a sink for the reactive metabolites, as demonstrated by Dansette et al., (1990, 2005) and Valadon et al., (1996). When comparing the metabolic fate of thiophene derivatives, a pattern emerges that involves the type (Mansuy et al., 1991), position (Dansette et al., 1990; Valadon et al., 1996; Rademacher et al., 2012) and number of substitution groups.
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2013, Bioorganic and Medicinal Chemistry LettersInvolvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats
2008, Toxicology LettersThe crucial protective role of glutathione against tienilic acid hepatotoxicity in rats
2008, Toxicology and Applied PharmacologyCitation Excerpt :Consistent with these gene expression changes, fluctuations in the hepatic GSH levels after the dosing of tienilic acid were shown in the present study. Previous studies using liver microsomal fractions have shown that tienilic acid is metabolized to 5-hydroxytienilic acid through hydroxylation of the thiophene ring by the hepatic drug-metabolizing enzyme CYP2C9 in humans, and similarly by CYP2C11 in rats (Mansuy et al., 1984; Dansette et al., 1990; Dansette et al., 1991). During this process, highly reactive electrophilic intermediates are formed, and hepatic glutathione is consumed in conjugation with the tienilic acid metabolites (Lopez-Garcia et al., 1994; Bonierbale et al., 1999).
Identification of liver protein targets modified by tienilic acid metabolites using a two-dimensional Western blot-mass spectrometry approach
2007, International Journal of Mass SpectrometryMonitoring drug-protein interaction
2006, Clinica Chimica Acta