Human Flavin-Containing Monooxygenase Form 2 S-Oxygenation: Sulfenic Acid Formation from Thioureas and Oxidation of Glutathione

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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 α-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 FMO2*1 allele may be at enhanced risk of pulmonary damage upon exposure to thioureas.

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