Study of Metabolic Interactions of Fipronil and Some CYP3A4 Substrates

Details

• Personal Author:
  Hodgson E ; Rose RL ; Tang J ; Usmani A
• Description:
  Fipronil, a highly active and broad spectrum insecticide from the phenyl pyrazole family, is a potent disruptor of the ?-aminobutyric acid (GABA)-gated chloride channel in the insect central nervous system. It owes its insect selectivity to the fact that it is less potent in binding the GABA receptor in mammals. Since its discovery about a decade ago, fipronil has been used against a variety of agricultural, domestic and veterinary insect pests. Despite its wide range of use, however, mammalian metabolism of fipronil has not been extensively investigated. The human metabolism of fipronil has been studied in our laboratory using human liver microsomes (HLM) and cytochrome P450 (CYP) isoforms. CYP3A4 has been identified as the major enzyme catalyzing fipronil metabolism in human. Because of broad substrate specificity of CYP3A4, fipronil may interact with many other CYP3A4 substrates. This study investigated metabolic interactions of fipronil with testosterone or diazepam, two other CYP3A4 substrates. Fipronil was incubated with testosterone or diazepam in HLM and metabolites were analyzed using HPLC. When 1.25, 5 or 20 ?M fipronil incubated with a serial concentrations of testosterone (0-200 ?M), activation of fipronil S-oxidation was observed using HLM as the enzyme source. Inhibition of testosterone 6?-hydroxylation was observed in HLM when incubating testosterone (4, 20, or 100 ?M) with fipronil (0-160 ?M). There were no significant effects of diazepam (0-400 ?M) on metabolism of fipronil (5, 20 or 80 ?M). However, when 6.25, 25 or 100 ?M concentrations of diazepam were incubated with fipronil (0-160 ?M), diazepam hydroxylation was not significantly affected although demethylation of diazepam was inhibited. These results demonstrate that fipronil has the potential to interact with other CYP3A4 substrates [Description provided by NIOSH]
• Subjects:
  Agriculture Amino Acids Enzymes Insecta Insecticides Laboratories Occupational Health Safety
• Keywords:
  Agricultural-chemicals Amino-acids Exposure-levels Insecticide-poisoning Insects Laboratory-testing Liver
• ISSN:
  1096-6080
• Publisher:
  Society of Toxicology
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Abstract or Summary
• 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
• Volume:
  78
• NIOSHTIC Number:
  nn:20025177
• Citation:
  Toxicologist 2004 Mar; 78(S-1):348
• Federal Fiscal Year:
  2004
• Performing Organization:
  East Carolina University
• Peer Reviewed:
  False
• Start Date:
  20010930
• Source Full Name:
  The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
• Supplement:
  S-1
• End Date:
  20080929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:44e1104fabf4459df78b2f41ef6d371e3e54e6fc074c30cfaf4e0934da103d349a21025c3e7b1675fc41cad1c37a431014923d9b10bfda0df065f9897b39cf68
• Download URL:
  https://stacks.cdc.gov/view/cdc/196660/cdc_196660_DS1.pdf
• File Type:
  [PDF - 52.11 KB ]