Jack A. Hinson, Ph.D.
Ph.D. – Vanderbilt University, 1972
Drug-induced liver toxicity is a significant problem in getting new drugs on the market. A major factor for this is that mechanisms of drug-induced liver toxicities are poorly understood. A significant focus of our laboratory is investigating mechanisms of liver toxicity (necrosis) produced by the commonly used analgesic/antipyretic drug acetaminophen. Acetaminophen is sold under a variety of trade names including Tylenol®. Whereas the drug is safe at therapeutic doses, in overdose it can produce a liver toxicity leading to death. The toxicity is mediated by conversion of the drug to a metabolite that reacts with glutathione leading to its depletion and covalently binds to protein. We have shown that these events lead to oxidative/nitrosative stress causing mitochondrial dysfunction and subsequent necrosis. We are investigating mechanisms of how the reactive metabolite induces oxidative/nitrosative stress and how these events cause mitochondrial dysfunction and death of the cell.
Recent Reserarch Support
NIH/NIDDK R01 DK079008 (04/01/09 – 03/31/14)
“Oxygen/Nitrogen Stress in Acetaminophen Hepatotoxicity”
NIH/NIDDK 1R01DK075936 (Co-I) (04/01/08 – 03/31/13)
“HIF-1alpha and VEGF in Acetaminophen Toxicity and Repair”
NIH/NIDDK R41 (Co-I) (08/01/11 – 07/31/14)
“Adduct Dipstick for Diagnosis of Acetaminophen Toxicity”
Agarwal R, Hennings L, Rafferty, TM, Letzig, LG, McCullough, S, James, LP, MacMillan-Crow LA, Hinson JA. Acetaminophen-induced hepatotoxicity and protein nitration in neuronal nitric-oxide synthase knockout mice. Journal of Pharmacology and Experimental Therapeutics. 340, 134-142, 2012 (PMID: 22001257).
Xi Y, Greenhaw J, Ali A, Shi Q, Roberts DW, Hinson JA, Mushelishvili BR, Pence LM, Ando Y, Sun J, Davis K, Salminen WF. Changes in mouse liver protein glutathionylation after acetaminophen exposure. Journal of Pharmacology and Experimental Therapeutics. 340, 360-368, 2012 (PMID: 22045778).
Agarwal R, MacMillan-Crow LA, Hennings L, Rafferty T, Letzig LG, McCullough S, James LP, Hinson JA. Acetaminophen-induced hepatotoxicity in mice occurs with inhibition of activity and nitration of mitochondrial manganese superoxide dismutase. Journal of Pharmacology and Experimental Therapeutics. 337:110–116, 2011 (PMID: 21205919).
Chaudhuri S, McCullough SS, Hennings L, Letzig L, Simpson PM, Hinson JA, James LP. Acetaminophen hepatotoxicity and HIF-1a induction in acetaminophen toxicity occurs without hypoxia. Toxicol Appl Pharmacol. 252, 211-220, 2011 (PMID: 21316383).
Donahower BC, McCullough SS, Simpson PM, Lamps L, Stowe CD, Kurten R, Hinson JA, James LP. Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. Journal of Pharmacology and Experimental Therapeutics. 334: 33-43, 2010 (PMID: 20363854).
Burke AS, MacMillan LA, Hinson JA. The role of reactive nitrogen species.in acetaminophen-induced mitochondrial damage and toxicity. Chemical Research in Toxicology. 23, 1286-1292, 2010 (PMID: 20578685).
Holthoff JH, WoodlingKA, Doerge DR, BurnsST, HinsonJA, Mayeux PR. Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of peroxynitrite. Biochemical Pharmacology. 80, 1260-1265, 2010 (PMID: 20599800).