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Mol Carcinog. 2003 Feb;36(2):67-73.

Exceptional activity of murine glutathione transferase A1-1 against (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-induced DNA damage in stably transfected cells.

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1
Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

Abstract

We have shown previously that the alpha class murine glutathione transferase (GST) isoenzyme mGSTA1-1, unlike other mammalian class alpha GSTs, is highly efficient in catalyzing the glutathione (GSH) conjugation of (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the ultimate carcinogenic metabolite of benzo[a]pyrene. The present studies were undertaken to determine the efficacy of mGSTA1-1 in cellular protection against (+)-anti-BPDE-induced DNA damage in HepG2 cells stably transfected with mGSTA1 cDNA. Untransfected HepG2 cells, vector-transfected HepG2 cells (HepG2-vector), and cells transfected with mGSTA4 cDNA (HepG2-mGSTA4), an alpha class murine GST isoenzyme with low (+)-anti-BPDE-GSH conjugating activity, were used as controls for comparison. Intracellular GSH conjugation of (+)-anti-BPDE was significantly higher in mGSTA1-1-overexpressing HepG2 cells (HepG2-mGSTA1) than in HepG2-vector or HepG2-mGSTA4 cells. The formation of DNA-adducts of (+)-anti-BPDE, following a 10-, 20-, or 30-min exposure to 0.1, 0.5, or 1.0 microM [3H](+)-anti-BPDE, was reduced significantly in cells transfected with mGSTA1-1 compared with HepG2-vector or untransfected HepG2 cells. Consistent with the results with purified protein, overexpression of mGSTA4-4 had no effect on (+)-anti-BPDE-induced DNA damage. The results of the present study indicated that mGSTA1-1 was exceptionally effective in affording protection against (+)-anti-BPDE-induced DNA damage in a cellular system.

PMID:
12557262
DOI:
10.1002/mc.10097
[Indexed for MEDLINE]

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