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rdf:type |
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lifeskim:mentions |
umls-concept:C0001128,
umls-concept:C0016333,
umls-concept:C0016360,
umls-concept:C0026336,
umls-concept:C0098361,
umls-concept:C0205409,
umls-concept:C0393026,
umls-concept:C1280500,
umls-concept:C1407029,
umls-concept:C1522492,
umls-concept:C1549542,
umls-concept:C1882726
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pubmed:issue |
9
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pubmed:dateCreated |
1997-12-5
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pubmed:abstractText |
We studied the effects of 5-ethynyluracil (GW776), a potent inactivator of dihydropyrimidine dehydrogenase, on the metabolism of 5-fluorouracil (5-FU), in particular with respect to formation of the toxic compounds fluoroacetate (FAC) and 2-fluoro-3-hydroxypropionic acid (FHPA), using fluorine-19 nuclear magnetic resonance and the isolated perfused rat liver model. Livers were perfused with 5-FU alone at a dose of 15 mg kg(-1) body weight or with 5-FU + GW776 at doses of 15 mg 5-FU kg(-1) body weight and 0.5 mg GW776 kg(-1) body weight injected 1 h before 5-FU. All 5-FU was metabolized in experiments with 5-FU alone whereas unmetabolized 5-FU represented 94% of the fluorinated compounds measured in experiments with 5-FU + GW776. GW776 modulated both the catabolic and the anabolic pathways of 5-FU, the most striking effect being on the degradative pathway. The amount of 5-FU catabolites decreased by a factor of 27 in the presence of GW776. The modulator led to a decrease in alpha-fluoro-beta-alanine (FBAL) formation by a factor of approximately 110, while fluoride ion formation decreased by a factor of approximately 10. By strongly lowering the metabolism of 5-FU into FBAL, GW776 circumvented the transformation of FBAL into toxic FAC and FHPA. 5-FU anabolites increased by a factor of approximately 7 in the presence of GW776. The level of free fluoronucleotides and 5-fluorouridine-5'-diphosphate sugars was increased up to fivefold. No incorporation of 5-FU into RNA could be measured in experiments with 5-FU alone whereas, although low (0.1% of 5-FU injected dose), it was detectable in experiments with 5-FU + GW776. These results suggest that GW776 may be useful for attenuating the not very common but serious cardiotoxic and/or neurotoxic side-effects of 5-FU that are probably due to FBAL metabolites.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-1346985,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-14425080,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-1467338,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-14891958,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-1544906,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-16348609,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-1637660,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-2128162,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-2858369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-2893719,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-2894959,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-2964897,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-3922650,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-4758902,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-5430334,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-6433643,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-659397,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-6846548,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-7503799,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-7858459,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-7905405,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-8137256,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-8193429,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-8248211,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-8274158,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9365165-8512588
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:issn |
0007-0920
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
76
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1170-80
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pubmed:dateRevised |
2010-9-10
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pubmed:meshHeading |
pubmed-meshheading:9365165-Animals,
pubmed-meshheading:9365165-Bile,
pubmed-meshheading:9365165-Enzyme Inhibitors,
pubmed-meshheading:9365165-Fluoroacetates,
pubmed-meshheading:9365165-Fluorouracil,
pubmed-meshheading:9365165-Lactic Acid,
pubmed-meshheading:9365165-Liver,
pubmed-meshheading:9365165-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9365165-Male,
pubmed-meshheading:9365165-Rats,
pubmed-meshheading:9365165-Rats, Wistar,
pubmed-meshheading:9365165-Uracil
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pubmed:year |
1997
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pubmed:articleTitle |
5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model.
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pubmed:affiliation |
Biomedical NMR Group, IMRCP Laboratory, Université Paul Sabatier, Toulouse, France.
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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