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 expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with Kms ranging from 7 to 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.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301, USA.
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Henderson
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301, USA.
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.affiliation: The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.affiliation: The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, USA; College of Pharmacy, Oregon State University, Corvallis, OR 97331-7301, USA; Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301, USA.
authors.forename: J Fred
authors.initials: JF
authors.lastname: Stevens
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kedzie
authors.affiliation: Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Wenkui K
authors.initials: WK
authors.lastname: Fang
authors.affiliation: Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Heidelbaugh
authors.affiliation: Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Phong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chow
authors.affiliation: Department of Chemical Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Garst
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, CA 92623-9534, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gil
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301, USA; The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-7301, USA; Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331-7301, USA. Electronic address: david.williams@oregonstate.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007313:Insecta; D051379:Mice; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013871:Thiones / Q000737:chemistry / Q000378:metabolism*; D013890:Thiourea / Q000737:chemistry / Q000378:metabolism*
chemical_list: D013871:Thiones; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D013890:Thiourea
keywords: Drug development; Flavin-containing monooxygenase; Thiones; Thioureas
references.citation: Drug Metab Rev. 2002 Aug;34(3):503-11
references.pmid: 12214662
references.citation: Pediatr Res. 2002 Feb;51(2):236-43
references.pmid: 11809920
references.citation: Drug Metab Dispos. 2009 Jan;37(1):178-86
references.pmid: 18948378
references.citation: Drug Metab Dispos. 2003 Feb;31(2):187-93
references.pmid: 12527699
references.citation: Pharmacogenetics. 2003 Aug;13(8):495-500
references.pmid: 12893987
references.citation: Chem Res Toxicol. 1995 Mar;8(2):166-81
references.pmid: 7766799
references.citation: Expert Opin Drug Metab Toxicol. 2006 Feb;2(1):41-9
references.pmid: 16863467
references.citation: Chem Res Toxicol. 2006 Mar;19(3):443-9
references.pmid: 16544950
references.citation: Toxicol Lett. 1991 Sep;58(1):37-41
references.pmid: 1832793
references.citation: J Biol Chem. 2002 Apr 12;277(15):12824-9
references.pmid: 11823459
references.citation: J Biol Chem. 1998 Nov 13;273(46):30599-607
references.pmid: 9804831
references.citation: Pharmacol Ther. 2005 Jun;106(3):357-87
references.pmid: 15922018
references.citation: Antimicrob Agents Chemother. 2007 Mar;51(3):1055-63
references.pmid: 17220416
references.citation: Drug Metab Dispos. 2000 Aug;28(8):1003-6
references.pmid: 10901713
references.citation: Drug Metab Dispos. 2007 Mar;35(3):328-30
references.pmid: 17142560
references.citation: Pharmaceuticals (Basel). 2012;5(11):1147-59
references.pmid: 23580869
references.citation: Drug Metab Rev. 2002 Aug;34(3):523-32
references.pmid: 12214664
references.citation: J Pharmacol Exp Ther. 1995 Mar;272(3):1293-9
references.pmid: 7891346
references.citation: Toxicology. 2004 Apr 15;197(2):81-91
references.pmid: 15003319
references.citation: Toxicol Appl Pharmacol. 2008 Dec 15;233(3):420-7
references.pmid: 18930751
references.citation: Biochem Pharmacol. 2008 Jan 15;75(2):570-9
references.pmid: 17942081
references.citation: Drug Metab Dispos. 2002 Jan;30(1):34-41
references.pmid: 11744609
references.citation: Biochem Pharmacol. 2004 Jul 1;68(1):73-83
references.pmid: 15183119
references.citation: Pharmacogenetics. 2004 Feb;14(2):117-30
references.pmid: 15077013
references.citation: J Pharmacol Exp Ther. 2002 Feb;300(2):355-60
references.pmid: 11805191
references.citation: Annu Rev Pharmacol Toxicol. 1982;22:321-39
references.pmid: 7044288
references.citation: J Antimicrob Chemother. 2006 Oct;58(4):768-72
references.pmid: 16895935
references.citation: Curr Drug Metab. 2003 Apr;4(2):151-70
references.pmid: 12678693
references.citation: Arch Biochem Biophys. 1979 Nov;198(1):78-88
references.pmid: 507850
references.citation: Chem Res Toxicol. 1991 Jul-Aug;4(4):482-9
references.pmid: 1912337
references.citation: Xenobiotica. 2006 Jul;36(7):645-57
references.pmid: 16864509
references.citation: Curr Opin Drug Discov Devel. 2003 Jul;6(4):486-93
references.pmid: 12951812
references.citation: Arch Biochem Biophys. 2007 Aug 15;464(2):251-9
references.pmid: 17531949
references.citation: Biochem Pharmacol. 2002 Jun 1;63(11):1941-8
references.pmid: 12093470
references.citation: Chem Res Toxicol. 2007 Apr;20(4):701-8
references.pmid: 17381136
references.citation: Drug Metab Dispos. 2000 Sep;28(9):1107-11
references.pmid: 10950857
references.citation: Pharmacogenet Genomics. 2005 Apr;15(4):245-56
references.pmid: 15864117
references.citation: Toxicol Appl Pharmacol. 2000 Nov 1;168(3):216-24
references.pmid: 11042094
references.citation: Chem Res Toxicol. 1992 Sep-Oct;5(5):726-33
references.pmid: 1446015
references.citation: Chem Res Toxicol. 2004 May;17(5):633-40
references.pmid: 15144220
references.citation: Drug Metab Dispos. 2004 Dec;32(12):1337-40
references.pmid: 15355885
references.citation: Chem Biol Interact. 1995 Apr 28;96(1):33-46
references.pmid: 7720103
references.citation: Chem Res Toxicol. 1999 May;12(5):396-402
references.pmid: 10328749
references.citation: Trends Pharmacol Sci. 2008 Jun;29(6):294-301
references.pmid: 18423897
references.citation: Pharmacogenet Genomics. 2008 Oct;18(10):877-86
references.pmid: 18794725
references.citation: Chem Biol Interact. 2011 Jun 30;192(1-2):21-5
references.pmid: 20863819
references.citation: Drug Metab Dispos. 2001 May;29(5):693-700
references.pmid: 11302936
references.citation: Drug Metab Rev. 1988;19(1):1-32
references.pmid: 3293953
references.citation: Mol Pharmacol. 1984 Jul;26(1):122-7
references.pmid: 6431260
references.citation: Chem Res Toxicol. 1990 Jul-Aug;3(4):372-6
references.pmid: 2133087