Effect of high dose of selenium nanoparticles on antioxidant system and biochemical profile of rats in correction of carbon tetrachloride-induced toxic damage of liver

Highlights

• Selenium nanoparticles capped by κ-carrageenan have negative surface charge.

• High doses of selenium nanoparticles can reduce the inflammation of liver.

• High doses of selenium normalize the formation of LPO products in toxic liver damage.

• Excess selenium in a healthy organism induces LPO process thus causing disorders in the urinary system.

Abstract

The ever-increasing application of selenium nanoparticles in medicine generates a need for thorough assessment of their effects on the living organism to prevent undesirable and dangerous toxic processes. The biological action of selenium nanoparticles strongly depends on the administrated dose. This stimulates in-depth study of possible mechanisms of their toxic effect, especially when they are applied in high doses. In this work, we have studied the effect of a high dose of selenium nanoparticles on rats and found that it is different in a healthy organism and in the case of modeled liver toxic damage. It has been revealed that the administration of a high dose of selenium nanoparticles to rats with toxic liver damage decreases the concentration of lipid peroxidation products in the blood and normalizes the level of liver enzymes at a time of the damage of the urinary system. At the same time, in a healthy organism, excess of selenium nanoparticles augments concentrations of urea, aspartate aminotransferase and malondialdehyde probably due to the fact that excess selenium nanoparticles induces the lipid peroxidation and damage the urinary system. However, the experiments show that, no mortality is observed among the animals treated with selenium in a dose of 6 times higher than the normal one. The use of sulfated polysaccharide κ-carrageenan as a stabilizer of nanoparticles generates a densely negative charge (ζ-potential −29 mV) on the nanoparticles surface. Probably, the high biocompatibility of nanoparticles is explained by the prolongation of their interaction with cells due to involvement of opsonization stage of negatively charged surface of nanoparticles into their metabolism.

Introduction

The increased interest of researchers in selenium nanoparticles (Se°NPs) is due to their promising applications in electronics, optics and especially in biomedical fields [[1], [2], [3]]. This is fairly confirmed by a sharp increase in the number of publications focused on synthesis, characterization, and study of biological effects of Se°NPs using various in vitro and in vivo models. In particular, Nguyen [4], Medina Cruz [5], Tran [6], and Vahdati [7] experimentally demonstrated the expressed antimicrobial activity of Se°NPs against Escherichia coli O157:H7, Staphylococcus aureus, and methicillin-resistant Staphylcoccus aureus, Pseudomonas auregiosa, Salmonella, and Listeria monocytogenes. Their antitumor activity and cytotoxicity against different lines of stomach adenocarcinoma cells as well as against A375 melanoma cells, MCF-7 breast adenocarcinoma cells, HepG2 hepatocellular carcinoma cells, Colo201 colon adenocarcinoma cells, PC-3 prostatic carcinoma cells, Hs68 human normal fibroblast cells, HK-2 proximal tubular cells and MCF-10A human mammary epithelial cells are discussed, in particular in works of Zeng [8] and Li [9]. Moreover, it is known that Se°NPs can neutralize the known model free radicals ABTS and DPPH, the superoxide anion (O₂^·−) generated from the xanthine/xanthine oxidase (X/XO) system, and ROS in living organism tissues [[10], [11], [12], [13], [14]]. The experimentally confirmed low toxicity (in comparison with other forms of selenium) [[15], [16], [17]] along with the expressed antimicrobial, antiradical, antitumor, and anti-inflammatory properties of Se°NPs allows to consider them as advanced highly effective substances for correction of a number of infectious, oncological, and inflammatory diseases, and also for compensation of selenodeficiency in animal organism. The majority of pharmacochemical transformations of Se°NPs and their translation into bioavailable organic forms (selenocysteine and selenomethionine) followed by their involvement into biosynthesis of various enzymes (glutathione peroxidase I, II, III, IV, 5-iodothyronyndeyodynase, thioredoxin reductase, phospholipid-hydroperoxide glutathione peroxidase), as well as selenoproteins P and W, proteins and peptides occur in the liver with the participation of its enzymatic systems [18,19]. Therefore, this organ can be represented as a target for directed effects of Se°NPs in case of its damage. The liver is the main detoxifying organ and is affected daily even in the absence of any external factors. Disorder of compensatory mechanisms of self-regeneration of the liver induces the primary inflammation (hepatitis) that without an adequate therapy leads to severe forms of necrosis, cirrhosis, various dystrophies and liver cancer. In addition, grave health conditions are caused by exposure of the liver to microbes, viruses, and toxins (endotoxins and exotoxins) [20,21]. A constant companion of pathological processes in the liver is intensification of free-radical reactions, e.g. the generation of reactive oxygen species ROS (O₂^--, H₂O₂, ON) and the growth of lipid peroxidation (LPO). This results in damage to cell membranes of hepatocytes and basic cell organelles, with subsequent DNA damage that triggers the cell death via apoptosis and necrosis [22]. One of the promising routes to neutralization of LPO products in the liver and correction of destructive changes associated with their aggressive effects is the application of Se°NPs as antiradical agents. Due to their small size and increased biological activity, they have high bioavailability and are able to be bound more intensively with transport proteins, and to be included in a highly specific synthesis of selenoproteins (glutathione peroxidases GPx1, GPx2, GPx3 and GPx4) directly involved in neutralization of free radicals in tissues. The direct participation of selenium in the antioxidant protection of organism is evidenced from a drastic increase of its daily requirement (from 50 to 100 micrograms to 600 micrograms for humans) during of infectious, oncological, and toxic diseases. In particular, Prystupa et al. [23] have reported on a lower selenium content in serum of patients with alcoholic cirrhosis and a higher concentration of proinflammatory and profibrotic cytokines-interleukin-6 and growth differentiation factor-15 than in healthy individuals. Liu et al. [24] have shown that the administration of Se-enriched prebiotic based on L. Acidophilus and S. Cerevisie at CCl₄-induced liver fibrosis decreases the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and simultaneously increases the content of gamma-glutamyltransferase (GGTP), superoxide dismutase (SOD) and glutathione as well as reduces the expression of α- smooth muscle actin, collagen and TGFβ1 and TIMP-1. Today, the variety of selenium forms and sources, including Se°NPs synthesized using various stabilizing matrices, requires the evaluation of their safety. Selenium is a toxic element, which, in case of overdosing the threshold value for a specific organism, can promote a number of disorders in homeostasis of the organism and cause serious overdose-associated symptoms. Taking into account the fine balance between the recommended and toxic (900 μg/day for humans) doses of selenium and the specifics of biotransformation and accumulation of Se°NPs in organism, a clear understanding of the processes occurring under conditions of Se°NPs excess, particularly in the treatment of liver damages, is an urgent challenge. As objects of research in this paper we have chosen Se°NPs stabilized by natural sulfated polysaccharide κ-carrageenan (κCG). Water solubility, availability, biocompatibility, as well as unique biological activity determine the prospects of (κCG) in the synthesis of nanoparticles. Also it is expected that (κCG)-derived nanocomposites might possess valuable properties [25,26].

In this paper we have studied the effect of high-dose selenium nanoparticles on antioxidant system of rats upon correction of the toxic damage of liver modeled by a fourfold injection of carbon tetrachloride.