Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay |
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Authors: | Romert, Lennart Dock, Lennart Jenssen, Dag Jernstr?m, Bengt |
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Affiliation: | Department of Genetic and Cellular Toxicology, Wallenberg Laboratory, University of Stockholm S-106 91 Stockholm, Sweden 1Institute of Environmental Medicine, Karolinska Institutet S-104 01 Stockholm, Sweden 2Department of Toxicology, Karolinska Institutet S-104 01 Stockholm, Sweden |
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Abstract: | This study deals with the role of glutathione transferase (GST)-mediatedconjugation of (+)-7ß,8 -dihydroxy-9 ,10 -oxy-7,8,9,10-tetrahydrobenzo[a]pyrene(BPDE) in two mammalian cell lines, human mammary carcinomacells (MCF-7) and rat hepatoma cells (H4IIE), in relation tothen-capacity to metabolize ()-trans-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene[()-BP-7,8-diol] to products that induce mutations inco-cultivated V79 cells. Both MCF-7 and H4IIE cells metabolized()-BP-7,8-diol to BPDE, but mutations in co-cultivatedV79 cells were only detected with MCF-7 cells. However, depletionof glutathione (GSH) in H4HE cells increased the mutagenidtyof ( )-BP-7,8-diol to a similar level to that found withMCF-7 cells. Measurements of GST activity using GSH and post-microsomalsupernatants from H4IIE, V79 and MCF-7 cells indicated a substantialdifference in conjugation capacity. Although preparations fromall three cell-lines showed GST activity with l-chloro-2,4-dlnitro-benzeneas the substrate, GST activity towards BPDE could only be detectedin supernatants from H4HE cells. This is consistent with thepresence of GST 7-7 an isoenzyme highly efficient hi catalysingBPDE-GSH conjugation. The difference in GSH-conjugation activitytowards BPDE was confirmed using intact H4IIE and MCF-7 cellsin culture. These results indicate that GSH-conjugation playsa pivotal role in mutagenesis induced by polycyclk aromatichydrocarbons (PAH). Accordingly, a deficiency in GSH-conjugationcapacity may be regarded as one important factor in defininga target cell population with an increased risk for tumour initiationfollowing exposure to PAH. |
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