The objective of our research is to understand the mechanisms by which drugs and chemicals produce cell and organ toxicity and the role of cellular cytoprotective mechanisms in modulating toxicity. The toxicity of most organic chemicals is associated with their biotransformation to reactive, electrophilic metabolites or stable, but toxic, metabolites that cause cell damage.

We are particularly interested in two aspects of chemical bioactivation: one, what is the chemical nature of the metabolites formed, and two, how is the formation of toxic metabolites coupled to the production of cell damage?

Several approaches are used to investigate the bioactivation of chemicals. Reaction mechanism studies are conducted to understand the metabolic pathways involved and to gain insight into the nature of reactive intermediates, which may be too short-lived to be isolated. Studies on the perturbation of cellular glutathione homeostasis are employed to examine the relationships between toxic metabolite formation and cell damage.

The techniques used include mass spectrometry and nuclear magnetic resonance spectroscopy to identify metabolites, in situ hybridization and in situ reverse-transcriptase polymerase chain reaction to map the distribution of bioactivation and cytoprotective pathways, and development of transfected cell lines to study drug-induced cell damage.

Present studies are focused on the glutathione-dependent, multistep pathway for the bioactivation of nephrotoxic and nephrocarcinogenic halogenated alkenes, on the metabolism and bioactivation of hydrochlorofluorocarbons, on the enzymology and regulation of glutathione biosynthesis and the mercapturic acid pathway.

Recent Publications

Xu L, Krenitsky DM, Seacat AM, Butenhoff JL, Tephly TR, Anders MW. 2006. N-Glucuronidation of Perfluorooctanesulfonamide by Human, Rat, Dog, and Monkey Liver Microsomes and by Expressed Rat and Human UDP-Glucuronosyltransferases. Drug Metab Dispos. May 23; Epub aead of print.

Fang YY, Kashkarov U, Anders MW, Board PG. 2006. Polymorphisms in the human glutathione transferase zeta promoter. Pharmacogenet Genomics. May;16(5):307-313.

Starr TB, Matanoski G, Anders MW, Andersen ME. 2006. Workshop overview: reassessment of the cancer risk of dichloromethane in humans. Toxicol Sci. May;91(1):20-28.

Blackburn AC, Matthaei KI, Lim C, Taylor MC, Cappello JY, Hayes JD, Anders MW, Board PG. 2006. Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant response pathways. Mol Pharmacol. Feb;69(2):650-657.

Sheu SS, Nauduri D, Anders MW. 2006. Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta. Feb;1762(2):256-265

Board PG, Anders MW. 2005 Human glutathione transferase zeta. Methods Enzymol. 401:61-77. Review.

Anders MW. 2005. Formation and toxicity of anesthetic degradation products. Annu Rev Pharmacol Toxicol. 45:147-176. Review.

Anders MW. 2004. Glutathione-dependent bioactivation of haloalkanes and haloalkenes. 2004. Drug Metab Rev. Oct;36(3-4):583-594.

Brookes PS, Yoon Y, Robotham JL, Anders MW, and Sheu SS. 2004. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. Oct;287(4):C817-833. Review.

Lim CE, Matthaei KI, Blackburn AC, Davis RP, Dahlstrom JE, Koina ME, Anders MW, and Board PG. 2004. Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases. Am J Pathol. Aug;165(2):679-693

Xu L, Krenitsky DM, Seacat AM, Butenhoff JL, and Anders MW. 2004. Biotransformation of N-ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide by rat liver microsomes, cytosol, and slices and by expressed rat and human cytochromes P450. Chem Res Toxicol. Jun;17(6):767-775.

Anderson WB, Board PG, and Anders MW. 2004. Glutathione transferase zeta-catalyzed bioactivation of dichloroacetic acid: reaction of glyoxylate with amino acid nucleophiles. Chem Res Toxicol. May;17(5):650-662.

Board PG, Taylor MC, Coggan M, Parker MW, Lantum HB, and Anders MW. 2003. Clarification of the role of key active site residues of glutathione transferase zeta/maleylacetoacetate isomerase by a new spectrophotometric technique. Biochem J. Sep 15;374(Pt 3):731-737.

Jolivette LJ, and Anders MW. 2003. Computational and experimental studies on the distribution of addition and substitution products of the microsomal glutathione transferase 1-catalyzed conjugation of glutathione with fluoroalkenes. Chem Res Toxicol. Feb;16(2):137-144.

Lantum HB, Cornejo J, Pierce RH, and Anders MW. 2003. Perturbation of Maleylacetoacetic Acid Metabolism in Rats with Dichloroacetic Acid-Induced Glutathione Transferase Zeta Deficiency. Toxicol Sci. Jul;74(1):192-202.