A particular antioxidant is critical to maintaining mitochondria, the organelles that make most of the energy for cells. Lawrence Lash, PhD, associate professor in pharmacology, is now embarking on his 11th year of investigation into that antioxidant.

“One of the major roles of the antioxidant glutathione is to protect cells from reactive oxygen species, and other toxic chemicals or drugs. The mitochondria are the primary target sites within the cell for many toxic chemicals, so maintenance of adequate glutathione levels is critical to maintaining the function of the mitochondria,” explained Dr. Lash. With a four-year, $900,000 grant from the National Institute of Diabetes and Digestive and Kidney Diseases, he hopes to learn more about the carrier proteins that shuttle glutathione into the mitochondria.

“Unlike other peptides or proteins, glutathione is produced by specific enzymes that are only found in the cytoplasm of the cells, so the glutathione has to be transported from the cytoplasm into the mitochondria,” he said. He and his research group have already learned that virtually all of the transport activity is accomplished by two carrier proteins, known as DCC and OGC (dicarboxylate and oxoglutarate carriers). “We’re working with a kidney cell line now and looking more at the molecular biology of the carrier proteins. We’ve cloned them and expressed them, and we’re going to do site-directed mutagenesis, where we are altering specific portions of the protein, putting them into the cell line, and seeing how they alter the function of the mitochondria and the susceptibility of the cells to different types of chemical injury.”

In particular, they are studying how changes in mitochondrial glutathione levels alter vulnerability to apoptosis, or cell death. “This has a lot of applicability for understanding how numerous chemicals produce toxicity in the kidneys and elsewhere,” he said. Kidney studies are particularly important because these organs are prominent targets for many antibiotics, analgesics, and other therapeutic chemicals, and also for environmental chemicals, such as trichloroethylene and other halogenated solvents.

Trichloroethylene has gained a high profile over the past few years through its connection to publicized polluted sites, Dr. Lash said. “Trichloroethylene is used in a lot of industrial processes, and it’s a major contaminant in all the Superfund waste sites. Because it also has important health consequences, there’s a lot of interest in it.” With a three-year, $500,000 grant from the National Institute for Environmental Health Sciences, he will be studying how exposure to the chemical evokes changes in human kidney cells.

“This trichloroethylene project is directly applicable to therapeutics and to human health-risk assessment,” he said, noting that he has been working with the Environmental Protection Agency on risk assessment for several years.

With the two funded grants for the glutathione and trichloroethylene projects, he plans to spend the next couple of years concentrating on his research and publishing his findings.  “I’m trying to catch up on papers from work done two years ago,” he added with a laugh. Since January, he has published 10 papers, and has plans to write at least eight more in the coming months.