title: Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis.
abstract: The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.
authors.affiliation: Department of Biochemistry, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
authors.forename: V K
authors.initials: VK
authors.lastname: Kolli
authors.affiliation: Department of Biochemistry, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
authors.forename: K
authors.initials: K
authors.lastname: Natarajan
authors.affiliation: Department of Anatomy, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
authors.forename: B
authors.initials: B
authors.lastname: Isaac
authors.affiliation: Department of Biochemistry, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
authors.forename: D
authors.initials: D
authors.lastname: Selvakumar
authors.affiliation: Department of Biochemistry, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India premilaabraham@cmcvellore.ac.in.
authors.forename: P
authors.initials: P
authors.lastname: Abraham
mesh_terms: D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D004751:Enteritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism* / Q000648:ultrastructure; D007421:Intestine, Small / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008727:Methotrexate; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase; D013997:Time Factors; D015431:Weight Loss
chemical_list: D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D013482:Superoxide Dismutase; D008727:Methotrexate
keywords: Methotrexate; mitochondrial dysfunction; rat; respiratory chain defects; small intestinal injury