Manifestation of toxic action of paracetamol in female and male rats depending on the circadian rhythms of liver activity

Abstract

Today, the toxicity of paracetamol is very common, this is due to both the widespread availability of the drug and the misconception of its high safety. Paracetamol poisoning is the most common cause of severe acute liver damage. Acute toxic hepatitis in rats of both sexes was simulated by administration of paracetamol at a dose of 1000 mg/kg of rat as a suspension in a 2% starch gel solution. The studied model of hepatitis was reproduced in chronodetermined mode, ie, the toxic dose of paracetamol was administered to rats at fixed hours and periods of the day: 09.00 (morning), 15.00 (day), 21.00 (evening), and 03.00 (night), so the model is interpreted as acute chronodetermined paracetamol-induced hepatitis (ACPH). In animals of the control pathology groups, blood sampling and liver isolation for further studies were performed 24 hours after administration of paracetamol. Based on the analysis of features of liver biorhythms changes depending on the period when acute hepatitis was modeled the circadian dependence of hepatotoxic action of paracetamol has been established. It has been found that modeling of hepatitis at night (03.00) was characterized by a medium degree of hepatotoxicity of paracetamol during the day. It has been established that the morning period (similar to the night period) was also characterized by a medium degree of cytotoxicity of paracetamol. The most pronounced suppression of liver function by the value of markers of cytolysis was observed in the simulation of pathology in the evening (21.00) in animals of both sexes. It has been determined that the least pronounced cytodestructive effect of paracetamol in the simulation of toxic hepatitis was observed at daytime (15.00). There are no intersex differences in the hepatotoxic effects of paracetamol on the example of female and male rats under the conditions of administration of paracetamol to animals in doses that exceeded therapeutic levels and led to the development of acute paracetamol hepatitis modeled in chronodetermined mode.