Morphological changes in the liver of rats after administration of chlorpromazine, depending on the dose and duration of administration

Abstract

Chlorpromazine (CPZ) remains a widely used drug in psychiatric practice today. The drug has a hepatotoxic effect, but the possible mechanisms of this side effect have not yet been fully elucidated. The aim of the study was to determine morphological changes in rat liver tissue under chronic toxic effects of chlorpromazine, depending on the dose and duration of its administration. The study was conducted on 60 sexually mature male rats. CPP was administered intragastrically at different doses (3.5, 7.0, 14.0 and 21.0 mg/kg) for 30 and 60 days. The material was fixed in a 10 % solution of neutral formalin (pH 7.2-7.4) for 24-48 hours, then passed through alcohols of increasing concentration and embedded in paraffin. Serial sections (6-7 µm thick) were prepared from the paraffin blocks and stained with hematoxylin-eosin and picrofuchsin by Van Gieson to determine the degree of fibrotic changes in liver tissue, as well as with Giemsa III to detect fatty degeneration of hepatocytes. The microscopic structure of the hepatic parenchyma was studied using an OLIMPUS BX41 light microscope at 100, 200 and 400x magnification. Morphometric parameters of structural changes were determined using an ocular grid and Image Tulsa 3.6 software. The data were statistically processed by descriptive statistics using the Microsoft Office Excel 2010 spreadsheet processor. When CPZ was administered in different doses and duration, pathological changes of varying severity developed in the liver tissue of rats. In the liver tissue, signs of intracellular and intra-tubular cholestasis are found mainly in the central lobes, accompanied by focal desquamation and proliferation of the biliary epithelium, formation of small-focal, less frequently zonal necrosis of hepatocytes, inflammatory infiltration of portal tracts with its spread to the interlobular stroma and parenchyma. Mitotically active binucleated hepatocytes are the key to the reparative process. Periductal fibrosis develops in the portal sections, marginal proliferation of the bile ducts, hepatocytes with signs of granular and/or fatty dystrophy are noted. In the central veins and vessels of the portal areas, moderate initial sclerotic changes were found, signs of their capillarisation in sinusoids, and the endothelium of the vessels had focal destructive changes. In all portal zones, proliferation of bile ducts and formation of bile pseudo-ducts were observed. Thus, the analysis of the morphometric study data showed that within 60 days of CPZ administration there is a significant increase in the relative volume of connective tissue and stromal-parenchymal index due to a significant decrease in the volume of hepatocytes.