In Vitro Sulfoxidation of Thioether Compounds by Human Cytochrome P450 and Flavin-Containing Monooxygenase Isoforms with Particular Reference to the CYP2C Subfamily

Details

• Personal Author:
  Hodgson E ; Karoly ED ; Rose RL ; Usmani KA
• Description:
  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 microM) as well as in HLMs. Ticlopidine, a CYP2C19 mechanism-based inhibitor, inhibited disulfoton sulfoxidation by CYP2C19 (IC50 after coincubation, 43.5 microM; IC50 after preincubation, 4.3 microM) 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. [Description provided by NIOSH]
• Subjects:
  Animals Insecticides Laboratories Occupational Health Safety
• Keywords:
  Animal-studies Humans In-vitro-studies Laboratory-animals Liver Models Pesticides
• ISSN:
  0090-9556
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; North Carolina ; OSHA Region 3 ; OSHA Region 4
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  333-339
• Volume:
  32
• Issue:
  3
• NIOSHTIC Number:
  nn:20029419
• Citation:
  Drug Metab Dispos 2004 Mar; 32(3):333-339
• Contact Point Address:
  Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695
• Federal Fiscal Year:
  2004
• Performing Organization:
  East Carolina University
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Drug Metabolism and Disposition
• End Date:
  20080929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7cb16f0749c6d07cc3f171496f60c33bcee4c406873af586e3a01ec02c6860ee62eb5e8e130302984c8614dd77a563013cadec3d80d0b18ac19cc2415bc60c30
• Download URL:
  https://stacks.cdc.gov/view/cdc/190404/cdc_190404_DS1.pdf
• File Type:
  [PDF - 1.75 MB ]