Inhibiting protein arginine deiminases has antioxidant consequences.
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Animals; Antioxidants; Cell Line, Tumor; Coculture Techniques; Colitis; DNA Damage; Dextran Sulfate; Epithelial Cells; Humans; Hydrolases; Macrophages; Male; Mice, Inbred C57BL; Ornithine
Biochemistry | Digestive System Diseases | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis. Therapeutics.
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Citation: J Pharmacol Exp Ther. 2015 Apr;353(1):64-70. doi: 10.1124/jpet.115.222745. Link to article on publisher's site
Witalison, Erin E.; Cui, Xiangli; Hofseth, Anne B.; Subramanian, Venkataraman; Causey, Corey P.; Thompson, Paul R.; and Hofseth, Lorne J., "Inhibiting protein arginine deiminases has antioxidant consequences." (2015). Thompson Lab Publications. 3.