Article
 

Flavin-Containing Monooxygenase S-Oxygenation of a Series of Thioureas and Thiones

Public Deposited

Downloadable Content

Download PDF
Request Accessible Version
https://ir.library.oregonstate.edu/concern/articles/m613n013w

Descriptions

Attribute NameValues
Creator
Abstract
  • Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC-MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2-7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with K[subscript m]s ranging from 7-160 μM and turnover numbers of 30-40 min⁻¹. The product formed was identified by LC-MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.
  • Keywords: Flavin-containing monooxygenase, Drug development, Thiones, Thioureas
Resource Type
DOI
Date Available
Date Issued
Citation
  • Henderson, M. C., Siddens, L. K., Krueger, S. K., Stevens, J. F., Kedzie, K., Fang, W. K., ... & Williams, D. E. (2014). Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones. Toxicology and Applied Pharmacology, 278(2), 91-99. doi:10.1016/j.taap.2014.04.002
Journal Title
Journal Volume
  • 278
Journal Issue/Number
  • 2
Rights Statement
Funding Statement (additional comments about funding)
  • This research was conducted with the assistance of the Mass Spectrometry Core of the Environmental Health Sciences Center (ES000210) at Oregon State University. The work was funded by PHS grant HL038650 (DEW).
Publisher
Peer Reviewed
Language
Replaces
Accessibility Feature

Relationships

Parents:

This work has no parents.

Items

Thumbnail Title Date Uploaded Visibility Actions
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure4B).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure5).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure6).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Table1).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Table2).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase.pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure1).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure2).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure3A).pdf 07/25/2017 Public
file details KruegerSharonEnviroMolecToxicolFlavinContainingMonooxygenase(Figure3B).pdf 07/25/2017 Public