title: Combination of tacrolimus and mycophenolate mofetil induces oxidative stress and genotoxicity in spleen and bone marrow of Wistar rats.
abstract: Tacrolimus (TAC) and mycophenolate mofetil (MMF) are common immunosuppressive drugs used to avoid immunological rejection of transplanted organs. The risk of developing cancer is the most critical complication in organ transplant recipients undergoing immunosuppressive therapy. This study aims to explore the cytotoxic and genotoxic effects of TAC and MMF alone or combined orally administrated on spleen and bone marrow of Wistar rats. Our results showed that TAC (2.4; 24 and 60mg/kg) and MMF (5; 50 and 125mg/kg) induced a genotoxic effect on rat bone marrow. Moreover, the co-treatment with the TAC/MMF (2.4/5mg/kg b.w.; 2.4/50mg/kg b.w. and 60/50mg/kg b.w.) produce a genotoxicity as measured by micronuclei (MN) frequencies, chromosomal aberrations (CA) rates and DNA damage levels. Furthermore, the TAC and MMF-treated animals developed oxidative stress in spleen, indicated by a significant increase of malondialdehyde (MDA), protein oxidation and decrease of anti-oxidant enzymes levels such as catalase (CAT) and superoxide dismutase (SOD). This damage was associated with an increase of DNA fragmentation. Co-treatment with TAC/MMF synergistically induced markers of oxidative stress in rat splenic tissue. In conclusion, TAC/MMF associated induction in oxidative stress plays a role in the splenic and bone marrow toxicity and enhances the different endpoints of genotoxicity, suggesting its mutagenic action in vivo.
authors: Laboratory of Research on Biologically Compatible Compounds, Faculty of Dental Medicine, 5019 Monastir, Tunisie. Electronic address: ferjani.hanenlrsbc@gmail.com.
authors: Hanen
authors: H
authors: Ferjani
authors: INRS-Institut Armand-Frappier, Laval, Québec, Canada; Department of Biochemistry, National Research Centre, Dokki, Cairo, Egypt.
authors: Hossam
authors: H
authors: Draz
authors: Laboratory of Research on Biologically Compatible Compounds, Faculty of Dental Medicine, 5019 Monastir, Tunisie.
authors: Salwa
authors: S
authors: Abid
authors: Department of Nephrology, Dialysis and Transplant, University Hospital of Sahloul, 4021 Sousse, Tunisie.
authors: Abedellatif
authors: A
authors: Achour
authors: Laboratory of Research on Biologically Compatible Compounds, Faculty of Dental Medicine, 5019 Monastir, Tunisie.
authors: Hassen
authors: H
authors: Bacha
authors: Laboratory of Research on Biologically Compatible Compounds, Faculty of Dental Medicine, 5019 Monastir, Tunisie.
authors: Imen
authors: I
authors: Boussema-Ayed
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D009153:Mutagens; D009173:Mycophenolic Acid; D016559:Tacrolimus
keywords: Bone marrow; Chromosomal aberration; Micronuclei; Mycophenolate mofetil; Spleen; Tacrolimus