Document Detail

Covalent modification of lipids and proteins in rat hepatocytes and in vitro by thioacetamide metabolites.
MedLine Citation:
PMID:  22667464     Owner:  NLM     Status:  MEDLINE    
Thioacetamide (TA) is a well-known hepatotoxin in rats. Acute doses cause centrilobular necrosis and hyperbilirubinemia while chronic administration leads to biliary hyperplasia and cholangiocarcinoma. Its acute toxicity requires its oxidation to a stable S-oxide (TASO) that is oxidized further to a highly reactive S,S-dioxide (TASO(2)). To explore possible parallels among the metabolism, covalent binding, and toxicity of TA and thiobenzamide (TB), we exposed freshly isolated rat hepatocytes to [(14)C]-TASO or [(13)C(2)D(3)]-TASO. TLC analysis of the cellular lipids showed a single major spot of radioactivity that mass spectral analysis showed to consist of N-acetimidoyl PE lipids having the same side chain composition as the PE fraction from untreated cells; no carbons or hydrogens from TASO were incorporated into the fatty acyl chains. Many cellular proteins contained N-acetyl- or N-acetimidoyl lysine residues in a 3:1 ratio (details to be reported separately). We also oxidized TASO with hydrogen peroxide in the presence of dipalmitoyl phosphatidylenthanolamine (DPPE) or lysozyme. Lysozyme was covalently modified at five of its six lysine side chains; only acetamide-type adducts were formed. DPPE in liposomes also gave only amide-type adducts, even when the reaction was carried out in tetrahydrofuran with only 10% water added. The exclusive formation of N-acetimidoyl PE in hepatocytes means that the concentration or activity of water must be extremely low in the region where TASO(2) is formed, whereas at least some of the TASO(2) can hydrolyze to acetylsulfinic acid before it reacts with cellular proteins. The requirement for two sequential oxidations to produce a reactive metabolite is unusual, but it is even more unusual that a reactive metabolite would react with water to form a new compound that retains a high degree of chemical reactivity toward biological nucleophiles. The possible contribution of lipid modification to the hepatotoxicity of TA/TASO remains to be determined.
Diganta Sarma; Heather Hajovsky; Yakov M Koen; Nadezhda A Galeva; Todd D Williams; Jeffrey L Staudinger; Robert P Hanzlik
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2012-06-15
Journal Detail:
Title:  Chemical research in toxicology     Volume:  25     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-17     Completed Date:  2013-01-29     Revised Date:  2013-09-20    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1868-77     Citation Subset:  IM    
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KA 66045, USA.
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MeSH Terms
Cells, Cultured
Chromatography, Thin Layer
Hepatocytes / cytology,  drug effects,  metabolism
Mass Spectrometry
Muramidase / chemistry*,  metabolism
Phosphatidylethanolamines / chemistry*,  metabolism
Rats, Sprague-Dawley
Thioacetamide / analogs & derivatives,  chemistry,  metabolism*,  toxicity
Grant Support
Reg. No./Substance:
0/Phosphatidylethanolamines; 2669-09-2/thioacetamide-S-oxide; 3026-45-7/1,2-dipalmitoyl-3-phosphatidylethanolamine; 62-55-5/Thioacetamide; EC

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