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Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Xenobiotica 1999; 29(9):899-907X

Abstract

1. To identify the cytochrome P450 (CYP) isoenzymes responsible for the major metabolic pathways of S-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (S-MTPPA) in man, the metabolism of S-MTPPA was examined using human liver microsomes and microsomes containing cDNA-expressed CYP isozymes (CYP1A2, 2A6, 2B6, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2E1 and 3A4). 2. S-MTPPA was mainly oxidized to the 5-hydroxylated metabolite of the thiophene ring (MA6) with human liver microsomes in the presence of NADPH. The formation of MA6 was inhibited by SKF 525-A, suggesting that CYP plays role in the formation of MA6. 3. Eadie-Hofstee plots for the 5-hydroxylation of S-MTPPA in the range 5-100 microM were linear for all samples studied, suggesting that the formation of MA6 by human liver microsomes follows simple Michaelis-Menten kinetics. Apparent Vmax = 1.42+/-0.64 nmol/min/mg protein; Km = 12+/-5 microM. 4. Among the CYP inhibitors examined (alpha-naphthoflavone, sulphaphenazole, omeprazole, quinidine and troleandomycin), sulphaphenazole (a CYP2C9 inhibitor) showed the most potent inhibitory effect on the 5-hydroxylation of S-MTPPA by human liver microsomes. 5. When incubated with microsomes containing cDNA-expressed CYP isozymes, S-MTPPA was substantially oxidized to MA6 only by CYP2C9. 6. These results suggest that formation of the major metabolite of S-MTPPA, MA6, in human liver microsomes is catalysed predominantly by a single CYP isoenzyme, namely CYP2C9.

Authors+Show Affiliations

Pharmacokinetic Research Section, Research and Development Laboratories, Maruho Co., Ltd, Kyoto, Japan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10548450

Citation

Taguchi, K, et al. "Identification of Human Cytochrome P450 Isoforms Involved in the Metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic Acid." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 29, no. 9, 1999, pp. 899-907.
Taguchi K, Konishi T, Nishikawa H, et al. Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. Xenobiotica. 1999;29(9):899-907.
Taguchi, K., Konishi, T., Nishikawa, H., & Kitamura, S. (1999). Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 29(9), pp. 899-907.
Taguchi K, et al. Identification of Human Cytochrome P450 Isoforms Involved in the Metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic Acid. Xenobiotica. 1999;29(9):899-907. PubMed PMID: 10548450.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. AU - Taguchi,K, AU - Konishi,T, AU - Nishikawa,H, AU - Kitamura,S, PY - 1999/11/5/pubmed PY - 1999/11/5/medline PY - 1999/11/5/entrez SP - 899 EP - 907 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 29 IS - 9 N2 - 1. To identify the cytochrome P450 (CYP) isoenzymes responsible for the major metabolic pathways of S-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (S-MTPPA) in man, the metabolism of S-MTPPA was examined using human liver microsomes and microsomes containing cDNA-expressed CYP isozymes (CYP1A2, 2A6, 2B6, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2E1 and 3A4). 2. S-MTPPA was mainly oxidized to the 5-hydroxylated metabolite of the thiophene ring (MA6) with human liver microsomes in the presence of NADPH. The formation of MA6 was inhibited by SKF 525-A, suggesting that CYP plays role in the formation of MA6. 3. Eadie-Hofstee plots for the 5-hydroxylation of S-MTPPA in the range 5-100 microM were linear for all samples studied, suggesting that the formation of MA6 by human liver microsomes follows simple Michaelis-Menten kinetics. Apparent Vmax = 1.42+/-0.64 nmol/min/mg protein; Km = 12+/-5 microM. 4. Among the CYP inhibitors examined (alpha-naphthoflavone, sulphaphenazole, omeprazole, quinidine and troleandomycin), sulphaphenazole (a CYP2C9 inhibitor) showed the most potent inhibitory effect on the 5-hydroxylation of S-MTPPA by human liver microsomes. 5. When incubated with microsomes containing cDNA-expressed CYP isozymes, S-MTPPA was substantially oxidized to MA6 only by CYP2C9. 6. These results suggest that formation of the major metabolite of S-MTPPA, MA6, in human liver microsomes is catalysed predominantly by a single CYP isoenzyme, namely CYP2C9. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/10548450/Identification_of_human_cytochrome_P450_isoforms_involved_in_the_metabolism_of_S_2_[4__3_methyl_2_thienyl_phenyl]propionic_acid_ L2 - http://www.tandfonline.com/doi/full/10.1080/004982599238146 DB - PRIME DP - Unbound Medicine ER -