QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Usmani, K. A. Articles by Rose, R. L. Search for Related Content PubMed PubMed Citation Articles by Usmani, K. A. Articles by Rose, R. L.

IN VITRO SULFOXIDATION OF THIOETHER COMPOUNDS BY HUMAN CYTOCHROME P450 AND FLAVIN-CONTAINING MONOOXYGENASE ISOFORMS WITH PARTICULAR REFERENCE TO THE CYP2C SUBFAMILY

Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina

Cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are major catalysts involved in the metabolism of xenobiotics. The sulfoxidation of the thioether pesticides, phorate, disulfoton, sulprofos, and methiocarb, was investigated. Using pooled human liver microsomes (HLMs), thioether compounds displayed similar affinities; however, phorate and disulfoton displayed higher intrinsic clearance rates than either sulprofos or methiocarb. The sulfoxidation of thioethers by HLMs was found to be predominantly P450-driven (85-90%) compared with FMO (10-15%). Among 16 cDNA-expressed human P450 isoforms and 3 human FMO isoforms examined, the following isoforms and their polymorphisms had the highest rates for sulfoxidation, as follows: phorate, CYP1A2, 3A4, 2B6, 2C9^*1, 2C18, 2C19, 2D6^*1, and FMO1; disulfoton, CYP1A2, 3A4, 2B6, 2C9^*1, 2C9^*2, 2C18, 2C19, 2D6^*1, and FMO1; sulprofos, CYP1A1, 1A2, 3A4, 2C9^*1, 2C9^*2, 2C9^*3, 2C18, 2C19, 2D6^*1, and FMO1; methiocarb, CYP1A1, 1A2, 3A4, 2B6, 2C9^*1, 2C19, 2D6^*1, and FMO1. Among these isoforms, members of the CYP2C subfamily often had the highest affinities and clearance rates. Moreover, sulfaphenazole, a CYP2C9 competitive inhibitor, inhibited disulfoton sulfoxidation by CYP2C9 (IC₅₀ 0.84 µM) as well as in HLMs. Ticlopidine, a CYP2C19 mechanism-based inhibitor, inhibited disulfoton sulfoxidation by CYP2C19 (IC₅₀ after coincubation, 43.5 µM; IC₅₀ after preincubation, 4.3 µM) and also in HLMs. Our results indicate that current models of the substrate binding site of the CYP2C subfamily would not effectively predict thioether pesticide metabolism. Thus, the substrate specificity of CYP2Cs is more extensive than is currently believed, and some reevaluation of structure-activity relationships may be required.

This article has been cited by other articles:

				H.-K. Lee, J.-K. Moon, C.-H. Chang, H. Choi, H.-W. Park, B.-S. Park, H.-S. Lee, E.-C. Hwang, Y.-D. Lee, K.-H. Liu, et al. STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS Drug Metab. Dispos., July 1, 2006; 34(7): 1090 - 1095. [Abstract] [Full Text] [PDF]

				M. F. Paine, H. L. Hart, S. S. Ludington, R. L. Haining, A. E. Rettie, and D. C. Zeldin THE HUMAN INTESTINAL CYTOCHROME P450 "PIE" Drug Metab. Dispos., May 1, 2006; 34(5): 880 - 886. [Abstract] [Full Text] [PDF]

				B. Furnes and D. Schlenk EXTRAHEPATIC METABOLISM OF CARBAMATE AND ORGANOPHOSPHATE THIOETHER COMPOUNDS BY THE FLAVIN-CONTAINING MONOOXYGENASE AND CYTOCHROME P450 SYSTEMS Drug Metab. Dispos., February 1, 2005; 33(2): 214 - 218. [Abstract] [Full Text] [PDF]

				S. K. Krueger, L. K. Siddens, S. R. Martin, Z. Yu, C. B. Pereira, E. T. Cabacungan, R. N. Hines, K. G. Ardlie, J. L. Raucy, and D. E. Williams DIFFERENCES IN FMO2*1 ALLELIC FREQUENCY BETWEEN HISPANICS OF PUERTO RICAN AND MEXICAN DESCENT Drug Metab. Dispos., December 1, 2004; 32(12): 1337 - 1340. [Abstract] [Full Text] [PDF]