Nitric Oxide and Acute Phase Proteins Are Involved in Pathogenesis of Mycophenolate Mofetil–Induced Gastrointestinal Disorders in Rats H. Malekinejad, H. Cheraghi, A. Alizadeh, M.H. Khadem-Ansari, A.A. Tehrani, and S. Varasteh ABSTRACT This study was designed to clarify the molecular mechanism(s) of mycophenolate mofetil (MMF)– induced gastrointestinal (GI) disorders. Forty-two adult Wistar rats were assigned to 7 groups including control and test hosts. The control animals received normal saline and the test animals various doses of MMF (10, 20, or 40 mg/kg) for 14 days, or MMF, aspirin, or lipopolysaccharide as single high doses (40, 200, and 1 mg/kg, respectively). To evaluate the GI disorders, are determined body weight gain, serum level of alkaline phosphatase (ALP), nitric oxide (NO), and acute phase proteins (APP). Additionally, we measured the duodenal NO content and myeloperoxidase activity. MMF administration resulted in a significant (P  .05) body weight loss and elevation of serum levels of ALP and NO. The duodenal NO content increased in the test groups with the highest levels among the aspirin-treated cohort. The myeloperoxidase activity and the serum level of APP were elevated among MMF- and aspirin-treated animals. Histopatho- logic examinations showed villous atrophy and inflammatory cells infiltration among MMF- treated animals. Our data suggested that the MMF-induced GI disorders were likely related to local inflammatory reactions, which may be attributed to elevated NO and myeloperoxidase activities that result in pathological injuries. Moreover, the biochemical alterations and histopathologic injuries due to MMF administration were similar to aspirin-induced local disorders rather than to lipopolysaccharide-induced systemic damage. M YCOPHENOLATE mofetil (MMF) the pro-drug of the immunosuppressant mycophenolic acid (MPA), is used to prevent acute organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplantations. MMF, the 2-morpholinoethyl ester of MPA, noncompeti- tively and reversibly inhibits inosine monophosphate dehy- drogenase (IMPDH). MMF is rapidly hydrolyzed to MPA, the active metabolite. 1 MMF improves long-term graft survivals, allowing reduc- tion of calcineurin inhibitor doses in chronic transplant nephropathy both in adults and children. 2 Although MMF is generally well tolerated, its adverse effects include infec- tions, leukopenia, and gastrointestinal disturbances. 3 Numer- ous studies have reported an enteric-coated formulation of mycophenolate sodium to reduce the gastrointestinal (GI) side effects of MMF. 4,5 Because GI disorders are important and crucial, MMF doses are generally adjusted according to GI tolerability and blood counts. 6,7 Pharmacokinetics studies on MMF have indicated that the plasma levels and area under the curve (AUC) values of MPA in pediatric patients were higher than expected and may be associated with a greater incidence of primarily GI side effects. High plasma MPA concentrations following MMF administration are associated with a low clearance, which in turn may be implicated at least partly in the production of the GI side effects. 8 However, one cannot exclude a local toxic mechanism. Clinical GI symptoms due to MMF administration mostly include abdominal pain, nausea, diarrhea, and vomiting. 9 –11 Although there is evidence showing MMF-induced GI disorders in animal models and humans there is however relatively little known about the pathogenesis of these From the Department of Pharmacology & Toxicology (H.M., H.C., A.A., S.V.), Faculty of Veterinary Medicine, Department of Clinical Biochemistry (M.H.K.-A.), Faculty of Medicine, and De- partment of Pathology (A.A.T.), Faculty of Veterinary Medicine, Urmia University, Urmia, Iran. Address reprint requests to Hassan Malekinejad, Associate Professor, Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran. E-mail: hassanmalekinejad@yahoo.com and h.malekinejad@urmia.ac.ir © 2011 by Elsevier Inc. All rights reserved. 0041-1345/–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2011.04.016 Transplantation Proceedings, 43, 2741–2746 (2011) 2741