Human flavin-containing monooxygenase form 2 S-oxygenation: sulfenic acid formation from thioureas and oxidation of glutathione

Chem Res Toxicol. 2004 May;17(5):633-40. doi: 10.1021/tx034253s.

Abstract

Thioureas are oxygenated by flavin-containing monooxygenases (FMOs), forming reactive sulfenic and/or sulfinic acids. Sulfenic acids can reversibly react with GSH and drive oxidative stress through a redox cycle. For this reason, thiourea S-oxygenation is an example of FMO-dependent bioactivation of a xenobiotic. Functional FMO2 is expressed in the lung of 26% of individuals of African descent and 5% of Hispanics but not in Caucasians or Asians. We have previously demonstrated that human FMO2.1 protein expressed in Sf9 microsomes has high activity toward a series of thioureas that are known or suspected lung toxicants including thiourea, 1-phenylthiourea, and ethylenethiourea. We now show by HPLC and LC-MS that 1-phenylthiourea and alpha-naphthylthiourea are converted to their sulfenic acids. GSH in the incubations at concentrations of 0.5-1.0 mM completely eliminated the sulfenic acid with resultant production of GSSG. These results indicate that individuals with the FMO21 allele may be at enhanced risk of pulmonary damage upon exposure to thioureas.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Ethnicity / genetics
  • Ethylenethiourea / toxicity
  • Flavins / chemistry
  • Glutathione / metabolism*
  • Humans
  • Lung / drug effects*
  • Lung / enzymology
  • Mass Spectrometry
  • Microsomes / metabolism
  • Oxidation-Reduction
  • Oxygenases / genetics
  • Oxygenases / metabolism*
  • Phenylthiourea / toxicity
  • Sulfenic Acids / metabolism*
  • Thiourea / metabolism*
  • Xenobiotics / metabolism

Substances

  • Flavins
  • Sulfenic Acids
  • Xenobiotics
  • Ethylenethiourea
  • Phenylthiourea
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Glutathione
  • Thiourea