Document Detail


The toxicity of opiates and their metabolites in HepG2 cells.
MedLine Citation:
PMID:  14597126     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The toxicity of codeine (C), codeinone (CO), morphine (M), oxycodone (OC), pholcodine (P) and pholcodine-N-oxide (P-NOX) was assessed in HepG2 cells by determining cell viability via the measurement of lactate dehydrogenase (LDH) leakage through the membrane, depletion of reduced glutathione (GSH) and measurement of total protein content. Incubation of C, M, OC, P or P-NOX with HepG2 cells resulted in no significant loss of cell viability, depletion of GSH or decreased total protein content. In contrast, with CO there was a marked depletion of GSH with significant differences from control cells (P<0.05) being detected after as little as 5 min. This effect preceded the loss of cell viability and the decrease in total protein content. To identify the cause of GSH depletion during incubations with CO, the incubation solutions were analysed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Analysis showed that a codeinone-glutathione conjugate (CO-SG) had been formed. This adduct was synthesised and characterised by LC/MS/MS and by nuclear magnetic resonance spectroscopy (NMR). CO-SG was quantified in the incubation solutions using the synthesised standard substance. Results obtained in this study support the hypothesis that the toxicity of CO may be partly due to GSH depletion. The absence of LDH leakage and GSH depletion in the incubations containing C or OC suggests, that the presence of both a double bond at Delta 7 and an adjoining keto-group in the 6-position are necessary to elicit the toxicity of M analogues with regard to GSH depletion.
Authors:
Mark Jairaj; David G Watson; M Helen Grant; Graham G Skellern
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemico-biological interactions     Volume:  146     ISSN:  0009-2797     ISO Abbreviation:  Chem. Biol. Interact.     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-11-04     Completed Date:  2003-12-16     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0227276     Medline TA:  Chem Biol Interact     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  121-9     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, John Arbuthnott Building, University of Strathclyde, Glasgow G4 0NR, UK.
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Survival / drug effects
Chromatography, Liquid
Glutathione / metabolism
Hepatocytes / drug effects*,  metabolism,  pathology
Humans
L-Lactate Dehydrogenase / metabolism
Liver Neoplasms
Narcotics / chemistry,  metabolism,  toxicity*
Proteins / metabolism
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Narcotics; 0/Proteins; 70-18-8/Glutathione; EC 1.1.1.27/L-Lactate Dehydrogenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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