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    
Abstract/OtherAbstract:
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.
Authors:
Stephen S Hecht; Jeannette Zinggeler Berg; J Bradley Hochalter
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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    
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / urine
Adult
Aged
Aged, 80 and over
Bay-Region, Polycyclic Aromatic Hydrocarbon
Female
Glutathione / metabolism*
Glutathione Transferase / genetics*
Hepatocytes / metabolism*
Humans
Male
Metabolic Detoxication, Phase II
Middle Aged
Neoplasms / genetics
Phenanthrenes / chemistry,  metabolism*,  urine
Polymorphism, Genetic
Grant Support
ID/Acronym/Agency:
CA-92025/CA/NCI NIH HHS; R01 CA092025/CA/NCI NIH HHS; R01 CA092025-07/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Phenanthrenes; EC 2.5.1.18/Glutathione Transferase; GAN16C9B8O/Glutathione; WYQ7N0BPYC/Acetylcysteine
Comments/Corrections

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