Faculty: Denis M. Grant, PhD
General Research Areas: Drug Metabolism and Mechanistic Toxicology
Molecular Mechanisms of Toxicant Biotransformation, Gene Regulation and Toxic Outcomes
In collaboration with the laboratory of Professor Jason Matthews at the University of Oslo, our current general interest is in studying the molecular mechanisms that underlie the pathological consequences of exposure to potential chemical toxicants. Such consequences include risk for side effects from drugs as well as risk for cancers and other diseases due to environmental or dietary exposures to chemicals. One class of environmental chemicals that have been of particular interest to us are the polycyclic aromatic hydrocarbons (PAHs). Exposure to PAHs occurs because of their ubiquity in the environment as by-products of chemical manufacturing processes, in cigarette smoke and in other combustion events. Epidemiological and animal studies have linked PAH exposure to a variety of disorders, including acute tissue damage, metabolic and immune dysfunction, endocrine disorders, inflammatory conditions, and cancers of a variety of tissues. Such toxicities are often triggered only after these chemicals have been bioactivated into cytotoxic and genotoxic electrophiles by drug-metabolizing enzymes. The cytochromes P450 (CYPs) are one key superfamily of drug-metabolizing enzymes that can convert PAHs into either safe or more toxic metabolites. The PAHs (as well as several structurally related endogenous and dietary chemicals) are also capable of inducing the expression of certain CYPs and other drug-metabolizing enzymes, as well as that of many other important intracellular pathway components, by acting as specific ligands for the aryl hydrocarbon receptor (AHR), a key nuclear transcription factor. However, AHR ligands are now also known to include many compounds of endogenous or dietary origin. Our overall goal is to understand how differences in levels of key transcriptional co-regulators affect AHR ligand mediated signaling, disposition and risk for toxicity. We use pharmacokinetic, biochemical, molecular biology, cell culture, transcriptomic, proteomic and analytical techniques in genetically modified strains of mice and rats, cultured cells, cloned genes and expressed gene products to analyze toxicant disposition, gene structure, gene regulation, enzyme function and toxicity endpoints.
One ongoing project focuses on elucidating the key role played by a protein called TCDD-inducible poly-ADP-ribose polymerase (TIPARP; PARP7) in providing a negative regulatory feedback loop to the transcriptional activation of AHR by both its exogenous and dietary ligands, and the therapeutic or toxic consequences of disrupting this negative feedback by TIPARP using genetic or pharmacological means.
Hutin D, Long AS, Sugamori KS, Shao P, Singh SK, Rasmussen M, Olafsen NE, Pettersen S, Grimaldi G, Grant DM, Matthews J (2021). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) catalytic mutant mice (TiparpH532A) exhibit increased sensitivity to TCDD-induced hepatotoxicity and lethality. Toxicol Sci, in press.
Rodriguez KM, Buch-Larsen SC, Kirby IT, Rodriguez Siordia I, Hutin D, Rasmussen M, Grant DM, David LL, Matthews J, Nielsen ML, Cohen MS. (2021). Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets. Elife 10:e60480
Rasmussen M, Tan S, Somisetty VS, Hutin D, Olafsen NE, Moen A, Anonsen JH, Grant DM, Matthews J. (2021). PARP7 and mono-ADP-ribosylation negatively regulate estrogen receptor α signaling in human breast cancer cells. Cells 10(3): 623.
Cho T, Bott D, Ahmed S, Hutin D, Gomez A, Tamblyn L, Zhou AC, Watts TH, Grant DM, Matthews J. (2019). 3-Methylcholanthrene induces chylous ascites inTCDD-inducible poly-ADP-ribose polymerase (TIPARP) knockout mice. Int J Mol Sci 20(9): pii: E2312.
Gomez A, Bindesboll C, Satheesh SV, Grimaldi G, Hutin D, MacPherson L, Ahmed S, Tamblyn L, Cho T, Nebb HI, Moen A, Anonsen JH, Grant DM, Matthews J (2018). Characterization of TCDD-inducible poly-ADP-ribose polymerase (TIPARP/ARTD14) catalytic activity. Biochem J 475(23): 3827-3846.
Hutin D, Tamblyn L, Gomez A, Grimaldi G, Soedling H, Cho T, Ahmed S, Lucas C, Kanduri C, Grant DM, Matthews J (2018). Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome. Toxicol Sci 165(2): 347-360.
Ahmed S, Bott D, Gomez A, Tamblyn L, Rasheed A, Cho T, MacPherson L, Sugamori KS, Yang Y, Grant DM, Cummins CL, Matthews J (2015). Loss of the mono-ADP-ribosyltransferase TIPARP increases sensitivity to dioxin-induced steatohepatitis and lethality. J Biol Chem 290(27): 16824-16840.
Department of Pharmacology and Toxicology
Room 4316, Medical Sciences Building
1 King's College Circle