Donald Reed

Emeritus Professor, Biochemistry and Biophysics
	Office: ALS Bldg Email: Phone: (541)-737-4438 Links: Pub Med Keywords: Biological Oxidations; Glutathione; Environmental Toxicology

Education

Research

Mechanisms involved with the body's cellular protective systems function to protect cells during exposure to environmental chemicals and drugs. The roles of glutathione and vitamin E as principal cellular constituents of these systems are being investigated with several major hypotheses. 1) Cellular protection by glutathione, a unique tripeptide in high natural body concentrations, allows maintenance of the cellular redox status of protein thiols. Studies here have shown that specific intracellular proteins undergo a thiol/disulfide redox change upon exposure of the cells to oxidizing agents such as hydrogen peroxide. These changes have led to the hypothesis that specific proteins exist in cells to participate in a protective system that could sustain cells under adverse conditions, e.g., destructive mechanisms of macrophages, ionizing radiation. 2) The protective antioxidant function of vitamin E in vivo, i.e., in the whole organism, has a threshold value in terms of tissue vitamin E content. With freshly isolated hepatocytes as a model cell system, it has been found that a threshold appears to exist. If the vitamin E level decreases to a level below that threshold, protective effects of vitamin E are lost due to a rapid consumption of available vitamin. 3) The changes in protein thiol redox status after loss of the protective systems of glutathione and vitamin E occur by an oxyradical mechanism and not by thiol/disulfide interchange reactions. In those hepatocytes that lack protective systems, normal levels of oxygen appear capable of very damaging events related to loss of protein thiols and membrane functions.

Once in the body, many chemicals foreign to the biologic system (xenobiotics) are activated to reactive intermediates by cytochrome P-450, i.e., to other more toxic forms. Investigations on bioactivation of xenobiotics by glutathione focus on two major solvents and fumigants, ethylene dichloride and ethylene dibromide, that undergo metabolism primarily by glutathione conjugation, which is catalyzed by glutathione S-transferases. The formation of S-(2-haloethyl)-glutathione conjugates leads to the nonenzymatic formation of the corresponding episulfonium ion, which is an alkylating agent. Thus, glutathione participates in a bioactivation of these compounds, which appears related to their mutagenic and possible carcinogenic properties rather than functions of protection. Macromolecular alkylation by this episulfonium ion is an important aspect of their toxicity.