Belghazi, Maya published the artcileUse of isotopes and LC-MS-ESI-TOF for mechanistic studies of tienilic acid metabolic activation, SDS of cas: 40180-04-9, the main research area is tienilate metabolic activation mechanism cytochrome P 450 2C9.
Tienilic Acid (TA) is a uricosuric drug marketed in 1978 and which caused a number of rare immunoallergic hepatitis. It was withdrawn in the U.S. in 1980, in France in 1992. Early batches of tienilic acid also contained 0.1-0.5 % tienilic acid isomer. Tienilic acid isomer (TAI) has been shown to be metabolized by cytochrome P 450 (CYP) into a reactive thiophene 1-oxide which either binds to proteins, or can be trapped by sulfur nucleophiles. Tienilic acid is metabolized by human CYP 2C9 into 5-hydroxytienilic acid (a major metabolite representing 70 % of the dose excreted in human urine) but it also forms (a) reactive metabolite(s) which binds covalently to CYP 2C9 and it is a mechanism based inhibitor of CYP 2C9. Adding glutathione to incubations decreases the covalent binding, but only to 1 mol/mol P 450. However the reactive metabolite of tienilic acid is still unknown. Recently it has been shown using ESI-LC-MS that CYP 2C9 binds ∼2 mol of TA in absence of GSH and only one in presence of 3 mM GSH. Two pathways of activation of the thiophene ring have been postulated: (A) the arene oxide pathway and (B) the thiophene 1-oxide (or thiophene S-oxide) pathway. In the case of thiophene, benzo(b)thiophene, tienilic acid isomer and several other thiophenes, metabolism through pathway B (thiophene 1-oxide) has been clearly demonstrated. The 1-oxide has only been isolated in the case of benzothiophene. Thus, the aim of the present study was to more carefully examine the metabolic oxidation of tienilic acid using HPLC-MS (LC-ESI-TOF mass spectroscopy) in order to determine which pathway (A or B) is involved in this oxidation For that purpose, labeling experiments with deuterated TA, 1802, 18H2O, and D2O were also performed.
Advances in Experimental Medicine and Biology published new progress about Enzymic oxidation. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, SDS of cas: 40180-04-9.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem