Journal Article

γ-Glutamyl transpeptidase and glutathione biosynthesis in non-tumorigenic and tumorigenic rat liver oval cell lines

Arthur Komlosh, Gloria Volohonsky, Noga Porat, Chen Tuby, Evgenia Bluvshtein, Pablo Steinberg, Franz Oesch and Avishay A. Stark

in Carcinogenesis

Volume 22, issue 12, pages 2009-2016
Published in print December 2001 | ISSN: 0143-3334
Published online December 2001 | e-ISSN: 1460-2180 | DOI:
γ-Glutamyl transpeptidase and glutathione biosynthesis in non-tumorigenic and tumorigenic rat liver oval cell lines

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Glutathione synthesis and growth properties were studied in the γ-glutamyl transpeptidase(GGT)-negative, non-tumorigenic rat liver oval cell line OC/CDE22, and in its GGT-positive, tumorigenic counterpart line M22. γ-Glutamylcysteine synthetase (GGCS) activities were comparable. Growth rates of M22 cells exceeded those of OC/CDE22 cells at non-limiting and limiting exogenous cysteine concentrations. A monoclonal antibody (Ab 5F10) that inhibits the transpeptidatic but not the hydrolytic activity of GGT did not affect the growth rates of OC/CDE22, and decreased those of M22 to the OC/CDE22 level. In GSH-depleted M22, but not in OC/CDE22 cells, the rate and extent of GSH repletion with exogenous cysteine and glutamine exceeded those obtained with exogenous cysteine and glutamate. With Ab 5F10, repletion with cysteine/glutamine was similar to that obtained with cysteine/glutamate. Repletion with exogenous GSH occurred only in M22 cells, and was abolished by the GGT inhibitor acivicin. Repletion with γ-glutamylcysteine (GGC) in OC/CDE22 was resistant to acivicin whereas that in M22 was inhibited by acivicin. Repletion with exogenous GSH or cysteinylglycine (CG) required aminopeptidase activity and was lower than that obtained with cysteine. Unless reduced, CG disulfide did not support GSH repletion. The findings are compatible with the notions that (i) GGT-catalyzed transpeptidation was largely responsible for the growth advantage of M22 cells at limiting cysteine concentration, and for their high GSH content via the formation of GGC from a γ-glutamyl donor (glutamine) and cyst(e)ine, and (ii) aminopeptidase/dipeptidase activity is rate-limiting in GSH repletion when GSH or CG serve as cysteine sources.

Keywords: Ab, antibody; AHF, altered hepatic foci; BSO, buthionine sulfoximine; cysteine or cystine; CG, cysteinylglycine; DMEM, Dulbecco's modified Eagle medium; GGC, γ-glutamylcysteine; GGCS, γ-glutamylcysteine synthetase; GGCyT, γ-glutamyl cyclotransferase; GGT, γ-glutamyl transpeptidase; GS, glutathione synthetase; GSH, glutathione; HBSS, Hank's balanced salt solution; HC, hepatocarcinogenesis; TP, transpeptidation

Journal Article.  6221 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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