Superfund Research Program

Glutathione Conjugation of Environmental Toxins

Project Leader: Michael J. Kelner
Grant Number: P42ES010337
Funding Period: 2000-2010

Project-Specific Links

Final Progress Reports

Year:   2004 

Dr. Kelner’s project focuses on the regulation of microsomal glutathione transferase (MGST) enzymes and their role in the nephrotoxicity and carcinogenicity of vicinal haloalkene environmental toxins.  The MGST enzymes are believed to play a role in the nephrocarcinogenicity toxicity of vicinal haloalkenes by converting these compounds to a cysteine-containing nephrotoxic moiety.  During the past year, Dr. Kelner’s laboratory completed studies demonstrating that  basal expression of MGST1 protein is primarily dependent upon SP1, but not SP3, which is in contrast to the regulation of other genes belonging to the MAPEG super gene family (MAPEG = Membrane Associated Proteins involved in Eicosanoid and Glutathione Metabolism).  Other members of the MAPEG family, such as prostaglandin E synthase-1 (PGES-1) appear to be dependent upon SP3 protein expression in conjunction with SP1 regulation.

In addition, studies on the murine MGST1 gene were completed.  The entire MGST1 gene was recovered from the 129/SvJ strain and a vector capable of producing MGST1 “knockout” (or null homozygous) mice created.  Tissue expression studies on the murine MGST1 gene were completed and compared to MGST2 and MGST3.  MGST1 is highly expressed in the liver and also in organs with high oxidative stress such as endocrine glands.  The MGST2 gene is expressed in a variety of internal organs with high activity in the pancreas.  The MGST3 gene is expressed at high amounts in the human heart and also in exocrine organs with high peroxidase activity and therefore exposed to constant oxidative stress (e.g. thyroid or salivary glands).

Currently the research team is in the process of producing transgenic cell lines overexpressing MGST1 to confirm the ability of this enzyme to protect against oxidative stress but also induce sensitivity to vicinal haloalkenes.

Other studies confirmed that both the human and mouse MGST1 gene are capable of responding transcriptionally to oxidative stress induced by peroxides or paraquat.  The mRNA of MGST1 and MGST3 are increased in response to oxidative stress, and this response occurs within 2 hours.  The response detected is actually higher than that noted for “classical antioxidant enzymes” such as superoxide dismutase-2 (SOD2), or glutathione peroxidase-4 (GPX4).  Together these studies indicate that MGST’s are not housekeeping genes, as previously proposed, but play an active role in determining how an organism responds to environmental stress.