Linked Life Data

14613716

Source:http://linkedlifedata.com/resource/pubmed/id/14613716

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2003-11-17
pubmed:abstractText
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats but not humans. Rat FDVE nephrotoxicity is attributed to FDVE glutathione conjugation and bioactivation of subsequent FDVE-cysteine S-conjugates, in part by renal beta-lyase. Although FDVE conjugation and metabolism occur in both rats and humans, the mechanism for selective toxicity in rats and lack of effect in humans is incompletely elucidated. This investigation measured FDVE S-conjugate cytotoxicity in cultured human proximal tubular HK-2 cells, and compared this with known cytotoxic S-conjugates. HK-2 cells were incubated with FDVE and its GSH, cysteine S-mercapturic acid, cysteine S-sulfoxide, and mercapturic acid sulfoxide conjugates (0.1-2.7 mM) for 24 h. Cytotoxicity was determined by lactate dehydrogenase (LDH) release, total LDH, and the ability of viable cells to reduce a tetrazolium-based compound (MTT). FDVE was cytotoxic only at concentrations >/=0.9 mM. No increase in LDH release was observed with either FDVE-GSH conjugate. The FDVE-cysteine conjugates S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine (DFEC) and (Z)-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-FFVC) caused significant differences in LDH release and MTT reduction only at 2.7 mM; (Z)-FFVC was slightly more cytotoxic. Both S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine sulfoxide (DFEC-SO) and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine sulfoxide ((Z)-N-Ac-FFVC-SO) caused slightly greater changes in LDH release or total LDH than the corresponding equimolar DFEC and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-N-Ac-FFVC) conjugates. In contrast to FDVE S-conjugates, S-(1,2-dichlorovinyl)-L-cysteine was markedly cytotoxic, at concentrations as low as 0.1 mM. These results show that human proximal tubular cells are relatively resistant to FDVE and FDVE S-conjugate cytotoxicity. This may partially explain the lack of FDVE nephrotoxicity in humans.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Anesthetics, Inhalation, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine, http://linkedlifedata.com/resource/pubmed/chemical/Ethers, http://linkedlifedata.com/resource/pubmed/chemical/Formazans, http://linkedlifedata.com/resource/pubmed/chemical/Glutathione, http://linkedlifedata.com/resource/pubmed/chemical/Hydrocarbons, Fluorinated, http://linkedlifedata.com/resource/pubmed/chemical/L-Lactate Dehydrogenase, http://linkedlifedata.com/resource/pubmed/chemical/MTT formazan, http://linkedlifedata.com/resource/pubmed/chemical/Methyl Ethers, http://linkedlifedata.com/resource/pubmed/chemical/Tetrazolium Salts, http://linkedlifedata.com/resource/pubmed/chemical/fluoromethyl..., http://linkedlifedata.com/resource/pubmed/chemical/sevoflurane
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0041-008X
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
193
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
55-65
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Cytotoxicity of S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether (Compound A) in a human proximal tubular cell line.
pubmed:affiliation
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't