title: Circadian variation in murine hepatotoxicity to the antituberculosis agent «Isoniazide».
abstract: The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects.
authors.affiliation: a Laboratory of Pharmacology , Faculty of Medicine, University of Monastir , Monatir , Tunisia .
authors.forename: Nouha
authors.initials: N
authors.lastname: Souayed
authors.affiliation: a Laboratory of Pharmacology , Faculty of Medicine, University of Monastir , Monatir , Tunisia .
authors.forename: Malek
authors.initials: M
authors.lastname: Chennoufi
authors.affiliation: a Laboratory of Pharmacology , Faculty of Medicine, University of Monastir , Monatir , Tunisia .
authors.forename: Fida
authors.initials: F
authors.lastname: Boughattas
authors.affiliation: b Laboratory of Histology Cytology and Genetics , Faculty of Medicine, University of Monastir , Monastir , Tunisia .
authors.forename: Zohra
authors.initials: Z
authors.lastname: Haouas
authors.affiliation: c Laboratory of Mycotoxines , Phycotoxines and Associated Pathologies, Faculty of Pharmacy, University of Monastir , Monastir , Tunisia .
authors.forename: Khira
authors.initials: K
authors.lastname: Maaroufi
authors.affiliation: d Laboratory of Biochimie , Faculty of Pharmacy , Monastir , Tunisia .
authors.forename: Abdelhedi
authors.initials: A
authors.lastname: Miled
authors.affiliation: e Laboratory of Biomonitoring of the Environment (LR01/ES14) , Faculty of Science Bizerta, University of Carthage , Bizerta , Tunisia , and.
authors.forename: Mosaddok
authors.initials: M
authors.lastname: Ben-Attia
authors.affiliation: a Laboratory of Pharmacology , Faculty of Medicine, University of Monastir , Monatir , Tunisia .
authors.forename: Karim
authors.initials: K
authors.lastname: Aouam
authors.affiliation: f Unit of Chronobiology, Foundation A.-de-Rothschild , Paris , France.
authors.forename: Alain
authors.initials: A
authors.lastname: Reinberg
authors.affiliation: a Laboratory of Pharmacology , Faculty of Medicine, University of Monastir , Monatir , Tunisia .
authors.forename: Naceur A
authors.initials: NA
authors.lastname: Boughattas
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D002940:Circadian Rhythm; D055870:Drug Chronotherapy; D004798:Enzymes / Q000378:metabolism; D007538:Isoniazid / Q000008:administration & dosage / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; D004798:Enzymes; D008315:Malondialdehyde; D007538:Isoniazid
keywords: Circadian rhythm; hepatotoxicity; histopathology; isoniazid; mice; stress oxidative