Document Detail

Preferential glutathione conjugation of a reverse diol epoxide compared to a bay region diol epoxide of phenanthrene in human hepatocytes: relevance to molecular epidemiology studies of glutathione-s-transferase polymorphisms and cancer.
MedLine Citation:
PMID:  19187038     Owner:  NLM     Status:  MEDLINE    
Bay region diol epoxides are recognized ultimate carcinogens of polycyclic aromatic hydrocarbons (PAH), and in vitro studies have demonstrated that they can be detoxified by conjugation with glutathione, leading to the widely investigated hypothesis that individuals with low activity forms of glutathione-S-transferases are at higher risk of PAH induced cancer, a hypothesis that has found at most weak support in molecular epidemiology studies. A weakness in this hypothesis was that the mercapturic acids resulting from the conjugation of PAH bay region diol epoxides had never been identified in human urine. We recently analyzed smokers' urine for mercapturic acids derived from phenanthrene, the simplest PAH with a bay region. The only phenanthrene diol epoxide-derived mercapturic acid in smokers' urine was produced from the reverse diol epoxide, anti-phenanthrene-3,4-diol-1,2-epoxide (11), not the bay region diol epoxide, anti-phenanthrene-1,2-diol-3,4-epoxide (10), which does not support the hypothesis noted above. In this study, we extended these results by examining the conjugation of phenanthrene metabolites with glutathione in human hepatocytes. We identified the mercapturic acid N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-L-cysteine (14a), (0.33-35.9 pmol/mL at 10 microM 8, 24 h incubation, N = 10) in all incubations with phenanthrene-3,4-diol (8) and the corresponding diol epoxide 11, but no mercapturic acids were detected in incubations with phenanthrene-1,2-diol (7), and only trace amounts were observed in incubations with the corresponding bay region diol epoxide 10. Taken together with our previous results, these studies clearly demonstrate that glutathione conjugation of a reverse diol epoxide of phenanthrene is favored over conjugation of a bay region diol epoxide. Since reverse diol epoxides of PAH are generally weakly or nonmutagenic/carcinogenic, these results, if generalizable to other PAH, do not support the widely held assumption that glutathione-S-transferases are important in the detoxification of PAH in humans.
Stephen S Hecht; Jeannette Zinggeler Berg; J Bradley Hochalter
Related Documents :
3400268 - Disposition of the plant phenol ellagic acid in the mouse following oral administration...
4066998 - Metabolism and pharmacokinetics of phenelzine: lack of evidence for acetylation pathway...
2815098 - The excretion of chlorophenylmercapturic acid, chlorophenols and a guanine adduct in th...
1793738 - Identification of nac-hcpc and nac-beta-cec, and qualitative analyses of sulphur amino ...
2074208 - Visualization of glycosaminoglycans in rat incisor extracellular matrix using a hyaluro...
2630098 - The major pectic arabinogalactan having activity on the reticuloendothelial system from...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  22     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-10-21     Completed Date:  2010-11-23     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  426-32     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Acetylcysteine / urine
Aged, 80 and over
Bay-Region, Polycyclic Aromatic Hydrocarbon
Glutathione / metabolism*
Glutathione Transferase / genetics*
Hepatocytes / metabolism*
Metabolic Detoxication, Phase II
Middle Aged
Neoplasms / genetics
Phenanthrenes / chemistry,  metabolism*,  urine
Polymorphism, Genetic
Grant Support
CA-92025/CA/NCI NIH HHS; R01 CA092025/CA/NCI NIH HHS; R01 CA092025-07/CA/NCI NIH HHS
Reg. No./Substance:
0/Phenanthrenes; EC Transferase; GAN16C9B8O/Glutathione; WYQ7N0BPYC/Acetylcysteine

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

Previous Document:  Circular dichroism spectra and electrophoretic mobility shift assays show that human replication pro...
Next Document:  Are Thermodynamic and Kinetic Stabilities Correlated? A Topological Index of Reactivity toward Elect...