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Title: Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones

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 expressedmore » in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with K{sub m}s ranging from 7 to 160 μM and turnover numbers of 30–40 min{sup −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.« less

Authors:
;  [1];  [2];  [2];  [3];  [3];  [4]; ; ; ; ;  [5];  [4];  [1];  [3];  [3]
  1. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301 (United States)
  2. The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301 (United States)
  3. (United States)
  4. Department of Biological Sciences, Allergan, Inc., Irvine, CA 92623-9534 (United States)
  5. Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534 (United States)
Publication Date:
OSTI Identifier:
22439780
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 278; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; GENOTYPE; GLUTATHIONE; INTESTINES; KIDNEYS; LIVER; LUNGS; MICE; SULFITES; THIOUREA

Citation Formats

Henderson, Marilyn C., Siddens, Lisbeth K., Krueger, Sharon K., Stevens, J. Fred, College of Pharmacy, Oregon State University, Corvallis, OR 97331-7301, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301, Kedzie, Karen, Fang, Wenkui K., Heidelbaugh, Todd, Nguyen, Phong, Chow, Ken, Garst, Michael, Gil, Daniel, Williams, David E., E-mail: david.williams@oregonstate.edu, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301. Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.04.002.
Henderson, Marilyn C., Siddens, Lisbeth K., Krueger, Sharon K., Stevens, J. Fred, College of Pharmacy, Oregon State University, Corvallis, OR 97331-7301, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301, Kedzie, Karen, Fang, Wenkui K., Heidelbaugh, Todd, Nguyen, Phong, Chow, Ken, Garst, Michael, Gil, Daniel, Williams, David E., E-mail: david.williams@oregonstate.edu, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, & Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301. Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones. United States. doi:10.1016/J.TAAP.2014.04.002.
Henderson, Marilyn C., Siddens, Lisbeth K., Krueger, Sharon K., Stevens, J. Fred, College of Pharmacy, Oregon State University, Corvallis, OR 97331-7301, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301, Kedzie, Karen, Fang, Wenkui K., Heidelbaugh, Todd, Nguyen, Phong, Chow, Ken, Garst, Michael, Gil, Daniel, Williams, David E., E-mail: david.williams@oregonstate.edu, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301. Tue . "Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones". United States. doi:10.1016/J.TAAP.2014.04.002.
@article{osti_22439780,
title = {Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones},
author = {Henderson, Marilyn C. and Siddens, Lisbeth K. and Krueger, Sharon K. and Stevens, J. Fred and College of Pharmacy, Oregon State University, Corvallis, OR 97331-7301 and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301 and Kedzie, Karen and Fang, Wenkui K. and Heidelbaugh, Todd and Nguyen, Phong and Chow, Ken and Garst, Michael and Gil, Daniel and Williams, David E., E-mail: david.williams@oregonstate.edu and The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301 and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301},
abstractNote = {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{sub m}s ranging from 7 to 160 μM and turnover numbers of 30–40 min{sup −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.},
doi = {10.1016/J.TAAP.2014.04.002},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 278,
place = {United States},
year = {Tue Jul 15 00:00:00 EDT 2014},
month = {Tue Jul 15 00:00:00 EDT 2014}
}