Lopez-Garcia, M. Pilar published the artcileThiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: Inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is thiophene derivative cytochrome P4502C9 suicide substrate; tienilate metabolite cytochrome P4502C9 suicide substrate; immunoallergic hepatitis tienilate metabolite cytochrome P4502C9.
Oxidation of tienilic acid (TA) by microsomes of yeast expressing two closely related human liver cytochrome P-450s (P 450), P 450 2C9 and 2C10, led to catalysis-dependent loss of activity of these P450s. Under identical conditions, oxidation of a tienilic acid isomer (TAI) failed to give any P 450 inactivation. The loss of P 450 activity during TA oxidation was concomitant with product (5-hydroxytienilic acid, 5-OHTA) formulation, showed pseudo-first-order and saturation kinetics, and was inhibited by an alternative substrate, tolbutamide. Covalent binding of TA metabolites to microsomal proteins occurred in parallel with enzyme inactivation and was partially inhibited by the presence of glutathione in the reaction medium. However, glutathione did not protect P 450 enzyme from inactivation. Thus, TA exhibited all of the characteristics of a mechanism-based inactivator for P 450 2C9 and 2C10 enzymes. The following kinetic parameters were determined in the case of P 450 2C10: t1/2,max = 3.4 min, kinact = 3.6 10-3 s-1, KI = 4.3 μM, kinact/K1 = 813 L mol-1 s-1, and partition ratio = 11.6. Moreover, a specific covalent binding of 0.9 mol of TA metabolite per mol of P 450 2C10 was found to occur before the complete loss of enzyme activity (in incubations performed in the presence of glutathione). A plausible mechanism for P 450 2C10 (2C9) inactivation during TA oxidation is proposed. It involves the intermediate formation of an electrophilic thiophene sulfoxide, which may react at position 5 of its thiophene ring either with H2O to give 5-OHTA or with a nucleophilic group of an amino acid residue of the P 450 active site, which results in its covalent binding to P 450 protein. This alkylation and inactivation of P 450 2C9 (2C10) by TA could be a starting point for the appearance of anti-P 4502C antibodies detected in patients treated with TA and suffering from immunoallergic hepatitis.
Biochemistry published new progress about Alkylation. 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem