Title

Inhibiting protein arginine deiminases has antioxidant consequences.

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

4-1-2015

Document Type

Article

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

Disciplines

Biochemistry | Digestive System Diseases | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

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.

Rights and Permissions

Citation: J Pharmacol Exp Ther. 2015 Apr;353(1):64-70. doi: 10.1124/jpet.115.222745. Link to article on publisher's site

Related Resources

Link to Article in PubMed