Department: Pharmacology, Physiology, and Toxicology
Research Clusters: Cancer Biology; Cardiovascular Disease, Obesity, and Diabetes; Toxicology and Environmental Health Sciences
Office: BBSC 435-G | Laboratory: BBSC 406
Phone: (304) 696-7332
Project 1. The effect of herbal agents on susceptibility to toxins: Billions of dollars are spent in the United States each year by individuals on nutritional and herbal supplements. We are investigating the mechanism for reduction of hepatic acetaminophen toxicity by S-adenosyl-l-methionine (SAMe). This project is important since acetaminophen is the number one cause of drug induced liver failure in the U.S. This project is evaluating the cellular effects of SAMe that are responsible for attenuating acetaminophen toxicity. We are also comparing SAMe to the currently used clinical treatment for acetaminophen to evaluate SAMe’s effectiveness.
Project 2. Evaluating methods to reduce the side effects of cancer chemotherapeutic drugs: This project is evaluating the protective effect of another natural product on cisplatin nephrotoxicity. Cisplatin is a widely used cancer chemotherapeutic agent. Unfortunately, the two principal side effects of cisplatin treatment are renal and peripheral nerve dysfunction. We have found an agent that can reduce the renal toxicity in isolated renal tissue. We are evaluating whether resveratrol impacts cell signaling or alters oxidative stress as part of its protective effect against cisplatin.
Project 3. Examination of the mechanism for kidney damage by a metabolite of acetaminophen (Tylenol): Acetaminophen is converted by enzymes in the liver to several different substances. One of these agents is toxic to the kidney. We are investigating the role of oxidative stress in induction of 4-aminophenol renal toxicity. Further studies are also evaluating possible agents to reduce renal toxicity. A second component of this project is to test the hypothesis that part of the mechanism for 4-aminophenol toxicity is mediated by protein modification. The proteins modified by 4-aminophenol, the sub cellular location of these proteins and the impact on cell function are being assessed to evaluate the mechanism of toxicity.
Project 4. Susceptibility to oxidative stress in diabetes: Over 1 in 50 Americans are diagnosed with diabetes mellitus. Diabetes is associated with a higher risk of kidney disease and renal failure. The predisposition to renal dysfunction may involve a defect in the ability to protect the kidney from damage by free radicals. A student would examine: a) the predisposition to renal damage by renal toxicants that are known to induce free radical damage; b) investigate the cellular and subcellular abnormalities induced by diabetes; c) initiate studies of possible interventions to slow the progression of renal dysfunction.
The following selections have been taken from 85 published peer reviewed papers and four book chapters.
J.M. Brown, John G. Ball, Michael Scott Wright, Stephanie Van Meter and Monica A. Valentovic. Novel protective mechanisms for S-adenosyl-l-methionine against acetaminophen hepatotoxicity: Improvement of key antioxidant enzymatic function. Toxicology Letters July 2012.
J.M. Brown, JG Ball, A Hogsett, T. Williams and M.A. Valentovic. Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity. Toxicol Appl Pharmacol. 2010 Aug 15;247(1):1-9.
R. C. Harmon, S.P. Duffy, M.V. Terneus, J.G. Ball and M.A. Valentovic. Characterization of a Novel Model for Investigation of Radiocontrast Nephrotoxicity. Nephrology, Dialysis and Transplantation Mar;24(3):763-8, 2009.
M.V. Terneus, A.B. Carpenter and M.A. Valentovic. Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on hepatic damage when administered after acetaminophen exposure. Toxicology. 2Feb 3;244(1):25-34, 2008.
M.V. Terneus, K.K. Kiningham, A.B. Carpenter, S.B. Sullivan and M.A. Valentovic. Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on acetaminophen hepatic toxicity. J Pharmacol Exp Ther. Jan; 320(1):99-107, 2007.
R.C. Harmon, K.K. Kiningham and M.A. Valentovic. Pyruvate reduces 4- aminophenol in vitro toxicity. Toxicol. Appl. Pharmacol. 213(2):179-86,2006.
M.A. Valentovic, N. Alejandro, A. B. Carpenter, P.I. Brown and K.S. Ramos. Streptozotocin (STZ) Diabetes enhances benzo(alpha)pyrene induced renal injury in Sprague Dawley rats. Toxicol. Lett. 164(3):214-20, 2006.
R.C. Harmon, M. V. Terneus, K. K. Kiningham and M. Valentovic, Time Dependent Effect of p-Aminophenol (PAP) Toxicity in Renal Slices and Development of Oxidative Stress. Toxicol Appl Pharmacol. 2005 209(1):86-94, 2005.