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Vol. 52, Issue 6, 958-965, 1997

Characterization of a Human Glutathione S-Transferase µ Cluster Containing a Duplicated GSTM1 Gene that Causes Ultrarapid Enzyme Activity

Roman A. McLellan, Mikael Oscarson, Anna-Karin Alexandrie, Janeric Seidegård, David A. Price Evans, Agneta Rannug, and Magnus Ingelman-Sundberg

Division of Molecular Toxicology (R.A.M., M.O., M.I.-S.) and Unit of Genetic Toxicology (A.-K.A., A.R.), Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden, National Institute for Working Life, 171 84 Solna, Sweden (A.-K.A., A.R.), The Wallenberg Laboratory and Astra Draco AB, 221 00 Lund, Sweden (J.S.), and C 123 Riyadh Armed Forces Hospital, Riyadh 11159, Kingdom of Saudi Arabia (D.A.P.E.)

The µ class glutathione S-transferase gene GSTM1 is polymorphic in humans, with approximately half of the Caucasian population being homozygous deleted for this gene. GSTM1 enzyme deficiency has been suggested to predispose people to lung and bladder cancer. Some people in a Saudi Arabian population, however, have been described previously with ultrarapid GSTM1 enzyme activity. Here we have evaluated the molecular genetic basis for this observation. Genomic DNA from two Saudi Arabian subjects exhibiting ultrarapid enzyme activity and from 13 Swedish subjects having null, one, or two GSTM1 genes were subjected to restriction fragment length polymorphism analysis using the restriction enzymes EcoRI, EcoRV, and HindIII and combinations thereof. Hybridization was carried out using a full-length GSTM1 cDNA or the 5' and 3' parts of the cDNA. The restriction mapping data revealed the presence of a GST µ cluster with two GSTM1 genes in tandem situated between the GSTM2 and GSTM5 genes. A quantitative multiplex polymerase chain reaction method, which simultaneously amplified a fragment of the GSTM1 gene and the beta -globin gene, was developed, and the genomic GSTM1 copy number was determined from the GSTM1/beta -globin ratio. This method clearly separated GSTM1 +/- subjects (ratios between 0.4 and 0.7) from GSTM1 +/+ subjects (ratios between 0.8 and 1.2). The two Saudi Arabians with ultrarapid GSTM1 activities had ratios of approximately 1.5, indicating that they carried three GSTM1 genes. These results demonstrate the existence of a novel µ class GST cluster containing a duplicated active GSTM1 gene causing ultrarapid enzyme activity.

Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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