Many chemicals and their corresponding cysteine S-conjugates, which are intermediates in the mercapturic acid pathway, are metabolized in vivo to cysteine S-conjugate sulfoxides and/or N-acetylcysteine S-conjugate sulfoxides. Previous work in this laboratory provided the first evidence for the involvement of flavin-containing monooxygenases (FMOs) in cysteine conjugate S-oxidase activities of rat and rabbit liver and kidney. Sulfoxidation of the cysteine S-conjugates of the industrial solvents trichloroethylene and tetrachloroethylene has also been shown to yield electrophilic sulfoxides that may contribute to the nephrotoxicity and carcinogenicity of these chemicals. Because there are currently five known FMO isoforms (identified as FMO1-5) and some of these isoforms exhibit gender- and tissue- dependent expression, the broad objective of the proposed is to characterize the relative contributions of FMO isoforms in the metabolism and toxicity of cysteine S-conjugates. Similar studies will be conducted with methionine and selenomethionine, structural analogues of cysteine S-conjugates which we have also identified as FMO substrates and are known to cause toxicity when given to animals at high levels. Specific experimental objectives are: 1) To isolate and characterize the substrate selectivities of rat hepatic and renal FMO3 and FMO4; 2) To characterize species-, gender-, and age-dependent expression of FMO4, and provide further characterization of FMO1 and FMO3 expression in liver and kidney; 3) To quantitate in vivo FMO activity in rats and mice using cysteine S-conjugates; 4) To characterize the toxicity associated with cysteine S-conjugate sulfoxides and selenomethionine oxide. The proposed studies will allow for a better understanding of FMO expression and the mechanisms of toxicity of cysteine S-conjugates and related chemical, leading to a more accurate assessment of human risk to these chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044295-06
Application #
2905460
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Scherbenske, M James
Project Start
1994-08-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Zeng, Fang-Mao; Liu, Ling-Yan; Zheng, Jin et al. (2016) Identification of a Fused-Ring 2'-Deoxyadenosine Adduct Formed in Human Cells Incubated with 1-Chloro-3-buten-2-one, a Potential Reactive Metabolite of 1,3-Butadiene. Chem Res Toxicol 29:1041-50
Liu, Xin-Jie; Zeng, Fang-Mao; An, Jing et al. (2013) Cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene and 1-chloro-3-buten-2-one, two alternative metabolites of 1,3-butadiene. Toxicol Appl Pharmacol 271:13-9
Irving, Roy M; Elfarra, Adnan A (2013) Mutagenicity of the cysteine S-conjugate sulfoxides of trichloroethylene and tetrachloroethylene in the Ames test. Toxicology 306:157-61
Sun, Liang; Pelah, Avishay; Zhang, Dong-Ping et al. (2013) Formation of fused-ring 2'-deoxycytidine adducts from 1-chloro-3-buten-2-one, an in vitro 1,3-butadiene metabolite, under in vitro physiological conditions. Chem Res Toxicol 26:1545-53
Irving, Roy M; Pinkerton, Marie E; Elfarra, Adnan A (2013) Characterization of the chemical reactivity and nephrotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide, a potential reactive metabolite of trichloroethylene. Toxicol Appl Pharmacol 267:1-10
Elfarra, Adnan A; Zhang, Xin-Yu (2012) Alcohol dehydrogenase- and rat liver cytosol-dependent bioactivation of 1-chloro-2-hydroxy-3-butene to 1-chloro-3-buten-2-one, a bifunctional alkylating agent. Chem Res Toxicol 25:2600-7
Irving, Roy M; Brownfield, Mark S; Elfarra, Adnan A (2011) N-biotinyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide as a potential model for S-(1,2-dichlorovinyl)-L-cysteine sulfoxide: characterization of stability and reactivity with glutathione and kidney proteins in vitro. Chem Res Toxicol 24:1915-23
Novick, Rachel M; Vezina, Chad M; Elfarra, Adnan A (2010) Isoform distinct time-, dose-, and castration-dependent alterations in flavin-containing monooxygenase expression in mouse liver after 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Biochem Pharmacol 79:1345-51
Barshteyn, Nella; Elfarra, Adnan A (2009) Formation of mono- and bis-Michael adducts by the reaction of nucleophilic amino acids with hydroxymethylvinyl ketone, a reactive metabolite of 1,3-butadiene. Chem Res Toxicol 22:918-25
Barshteyn, Nella; Elfarra, Adnan A (2009) Mass spectral analyses of hydroxymethylvinyl ketone-hemoglobin adducts formed after in vivo exposure of Sprague-Dawley rats to 3-butene-1,2-diol. Chem Res Toxicol 22:1163-71

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