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.

Circadian Clock Is Involved in Regulation of Hepatobiliary Transport Mediated by Multidrug Resistance-Associated Protein 2

“…Interestingly, a few Mrp2 substrates such as methotrexate, isoniazid, and mycophenolate mofetil showed varying hepatotoxicity according to the dosing time of day. [42][43][44] Until now, the mechanism of this time-dependent toxicity has been unclear, and circadian rhythm in oxidative stress processes has occasionally been proposed as a possible explanation. However, the present results suggest that the time-dependent liver toxicity might be explained by circadian liver exposure because the liver toxicity of methotrexate, isoniazid, and mycophenolate mofetil was observed after administration in the beginning or middle of the light phase when the expression and function of Mrp2 were downregulated according to this study.…”

Molecular Mechanisms Involved in Oxidative Stress-Associated Liver Injury Induced by Chinese Herbal Medicine: An Experimental Evidence-Based Literature Review and Network Pharmacology Study

“…Therefore, whether ROS is linked to orchestrated biological processes in routine metabolism or initiation of oxidative stress depends on the steady or imbalance of redox state. Aside from the beneficial effects, disruption of redox homeostasis, by chemicals in general, is correlated to the moderate-to-severe damage in organisms which, in turn, accelerates the progression of oxidative stress-related impairment [ 21 ].…”

Circadian Clock Gene Expression and Drug/Toxicant Interactions as Novel Targets of Chronopharmacology and Chronotoxicology

“…The hepatotoxic potential of antituberculosis drug isoniazid varied when it was administered at ZT1, ZT9, and ZT17, and the toxicity was highest when isoniazid was given at ZT1 [48].…”