title: Circadian variation of cytotoxicity and genotoxicity induced by an immunosuppressive agent "Mycophenolate Mofetil" in rats.
abstract: Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.
authors.affiliation: a Laboratory of Pharmacology, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Ichrak
authors.initials: I
authors.lastname: Dridi
authors.affiliation: b Laboratory of Histology Embryology and Cytogenetic, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Intissar
authors.initials: I
authors.lastname: Grissa
authors.affiliation: b Laboratory of Histology Embryology and Cytogenetic, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Lobna
authors.initials: L
authors.lastname: Ezzi
authors.affiliation: b Laboratory of Histology Embryology and Cytogenetic, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Sana
authors.initials: S
authors.lastname: Chakroun
authors.affiliation: a Laboratory of Pharmacology, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Wafa
authors.initials: W
authors.lastname: Ben-Cherif
authors.affiliation: b Laboratory of Histology Embryology and Cytogenetic, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Haouas
authors.affiliation: a Laboratory of Pharmacology, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Karim
authors.initials: K
authors.lastname: Aouam
authors.affiliation: c Laboratory of Biomonitoring of the Environment, Faculty of Science of Bizerte , Carthage University , Tunis , Tunisia.
authors.forename: Mossadok
authors.initials: M
authors.lastname: Ben-Attia
authors.affiliation: d Unit of Chronobiology , Foundation A. de Rothschild , Paris Cedex , France.
authors.forename: Alain
authors.initials: A
authors.lastname: Reinberg
authors.affiliation: a Laboratory of Pharmacology, Faculty of Medicine , University of Monastir , Monastir , Tunisia.
authors.forename: Naceur A
authors.initials: NA
authors.lastname: Boughattas
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002875:Chromosomes / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008297:Male; D015162:Micronucleus Tests; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid
keywords: Circadian rhythm; cytotoxicity; genotoxicity; immunosuppressive agent; rats