title: Intestinal toxicity of oral warfarin intake in rats.
abstract: Though warfarin is extensively used in the prevention and treatment of thromboembolic processes in humans, adverse effects of warfarin therapy have been recognized. Intestinal hemorrhage is one of the hazards of anticoagulant therapy, but the mechanisms of warfarin toxicity are virtually unknown. In this work, the effects of 30 days oral warfarin (0.35 mg/l and 3.5 mg/l) intake on rat's gut were examined. Both doses resulted in prolongation of prothrombin time. Systemic effects of higher warfarin dose (increases in plasma AST, proteinuria, hematuria, changes in peripheral blood hematological parameters) were seen. Warfarin intake resulted in histologically evident tissue damage, leukocyte infiltration and intestinal inflammation [increases in myeloperoxidase activity, malondialdehyde content, superoxide dismutase and catalase activity, proinflammatory cytokine (IFN-γ, IL-17) concentrations in intestinal homogenates]. In contrast, suppression of gut-draining mesenteric lymph node (MLN) cell activity [proliferation responsiveness, production of IFN-γ and IL-17 to T lymphocyte mitogen Concanavalin A stimulation] was noted. Inhibition of regulatory cytokine IL-10 production by MLN cells, suggests commitment of MLN to the suppression of all inflammatory activities and creation of the microenvironment which is non-permissive for induction of potentially harmful immune response. These novel findings indicate the need of staying alert for (adverse) effects of warfarin therapy.
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mirkov
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Popov Aleksandrov
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Demenesku
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ninkov
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia.
authors.forename: Dina
authors.initials: D
authors.lastname: Mileusnic
authors.affiliation: Institute for Pathology, Military Medical Academy, 17 Crnotravska, 11000 Belgrade, Serbia.
authors.forename: Lidija
authors.initials: L
authors.lastname: Zolotarevski
authors.affiliation: Institute for Medical Biochemistry, Military Medical Academy, 17 Crnotravska, 11000 Belgrade, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Subota
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia; Institute of Zoology, Faculty of Biology, University of Belgrade, 16 Studentski trg 11000 Belgrade, Serbia.
authors.forename: Dragan
authors.initials: D
authors.lastname: Kataranovski
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 142 Bulevar despota Stefana, 11000 Belgrade, Serbia; Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, 16 Studentski trg, 11000 Belgrade, Serbia. Electronic address: milena@ibiss.bg.ac.rs.
authors.forename: Milena
authors.initials: M
authors.lastname: Kataranovski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014859:Warfarin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000925:Anticoagulants; D020381:Interleukin-17; D014859:Warfarin; D007371:Interferon-gamma
keywords: Intestinal inflammation; Mesenteric lymph nodes; Oral warfarin intake; Rats