Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats.

Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats' fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.

Epigenetic changes in the rat livers induced by pyrazinamide treatment.

Drug-induced liver injury, including drug-induced hepatotoxicity during the treatment of tuberculosis infection, is a major health problem with increasingly significant challenges to modern hepatology. Therefore, the assessment and monitoring of the hepatotoxicity of antituberculosis drugs for prevention of liver injury are great concerns during disease treatment. The recently emerged data showing the ability of toxicants, including pharmaceutical agents, to alter cellular epigenetic status, open a unique opportunity for early detection of drug hepatotoxicity. Here we report that treatment of male Wistar rats with antituberculosis drug pyrazinamide at doses of 250, 500 or 1000 mg/kg/day body weight for 45 days leads to an early and sustained decrease in cytosine DNA methylation, progressive hypomethylation of long interspersed nucleotide elements (LINE-1), and aberrant promoter hypermethylation of placental form glutathione-S-transferase (GSTP) and p16(INK4A) genes in livers of pyrazinamide-treated rats, while serum levels of bilirubin and activity of aminotransferases changed modestly. The early occurrence of these epigenetic alterations and their association with progression of liver injury specific pathological changes indicate that alterations in DNA methylation may be useful predictive markers for the assessment of drug hepatotoxicity.

[Polyamines and collagenes interaction in different processes of extracellular matrix production and functioning in norm and with pathology].

A great file of experimental data on tight interrelations between polyamines and main components of extracellular matrix (collagenes, laminin, fibronectin, etc.) metabolisms has been accumulated in the recent twenty years. Consequences of such tight interaction of collagenes, polyamines, enzymes of their metabolisms during formation and functioning of extracellular matrix are realised not only at a cellular level (proliferation, differentiation, adhesion, apoptosis), but also at the level of the whole organism (immunity, connective tissues and skeleton formation, tumors). Search for the ways of cells behavior modulation via influence on the levels of polyamines and contents of extracellular matrix at present is new direction in pharmacology of antitumor preparations that enables regulation of organism-tumor relationships, inhibition of angiogenesis, tumor growth and metastasing.

[Collagen transformation in organism: modern state of the problem]. / Preobrazovanie kollagenov v organizme: sovremennoe sostoianie problemy.

Collagens, which compose 1/3 of total proteins in the organism, have unique chemical structure and biological role. Current state of the investigation of these proteins biosynthesis and catabolism, role of shaperones, prolyl- and lysiloxydases, glycosyltransferases, metalloproteinases and other enzymes in collagens metabolism, as well as biological activities of collagens and their fragments have been considered in the review.

[Antioxidant effectiveness of short-chain alpha-tocopherol acetate in acute paracetamol poisoning in rats]. / Antioksydantna efektyvnist' pokhidnoho alpha-tokoferolatsetatu z ukorochnym bichnym lantsiuhom za umov hostroho otruiennia shchuriv paratsetamolom.

In the experiments in vivo on white rats possibility of paracetamol hepatotoxic effects correction with synthetic short-chain alpha-tocopherol derivative and pharmacopeial preparation of vitamin E has been studied. Levels of superoxide anion generation in liver mitochondria fraction, catalase activity and reduced glutathione, serum aminotransferase and alcaline phosphatase activities and liver subcellular fractions lipid contents were investigated. It was shown that the short-chain vitamin E derivative and pharmacopeial preparation had a membranotropic effect, normalizing free and total cholesterol levels in liver mitochondria fraction and decreasing serum aminotransferase activity level. Investigated compounds also decreased levels of superoxide anions generation, increased catalase activity and level of reduced glutathione in liver. Antioxidative properties of this derivative and pharmacopeial preparation were demonstrated both at the primary (dienes, trienes) and at final steps of lipid peroxidation (TBA-products formation). This antioxidative activity of alpha-tocopherol acetate and its derivative depended on the structure of chromane cycle but not on the length of side chain.

[Structure and metabolism of collagens in various pathologies]. / Struktura i obmen kollagenov pri razlichnykh patologiiakh.

Collagen constitutes approximately one third of the body's proteins; it has different functions, and changes in its metabolism and structure accompany almost every pathologic process. This article reviews basic knowledge of the alterations and defects in collagen metabolism and structure which give rise to a number of heritable and acquired diseases, their causes and consequences.

[Effect of 1,25-dihydroxyvitamin D3 on 15-lipoxygenase activity]. / Vliianie 1,25-dioksivitamina D3 na aktivnost' 15-lipoksigenazy.

The influence of 1.25-dihydroxyvitamin D3 on soybean 15-lipoxygenase activity was studied in vitro. 1.25-Dihydroxyvitamin D3 inhibited enzymatic activity in relation to its dose, pH and substrate (linoleic acid) concentration; the findings are indicative of a mixed type of inhibition.

[A hormonally-active form of vitamin D3--1,25-dihydroxyvitamin D3--an inhibitor of leukocyte lipoxygenase]. / Gormonal'no-aktivnaia forma vitamina D3--1,25-dioksivitamin D3-- ingibitor leikotsitarnoi lipoksigenazy.

The effect of the hormonally active vitamin D3 formulation on the activity of porcine leukocyte lipoxygenase was studied. The rate of enzyme inhibition was vitamin dose-dependent and increased if pH values raised, while the vitamin inhibitory effect was decreased as the content of linoleic acid used as a substrate was increased.