USING OF CELL LINE HepG2 FOR ASSESSMENT OF TOXIC AND METABOLIC EFECTS OF ANTIPSYCHOTIC DRUGS.

In order to study in vitro the toxic and metabolic effects of antipsychotic drugs (AP) on the cells of hepatic origin we used human hepatoblastoma cell line HepG2. We cultured HepG2 cells in the presence of two AP of the first and second generations (haloperidol and olanzapine, respectively) adding them to the culture medium in concentrations that may at the therapeutic use of AP take place in liver and other tissues of a high lipid content. In the process of cultivation, we detected several products of carbohydrate and lipid metabolism, measured activity of four hepatocellular enzymes in the culture medium, and estimated cell viability/proliferation in the MTS-test. We observed that both AP performed a toxic effect on HepG2 cells, the effect was manifested by a decrease in cell viability/proliferation and an increase in alkaline phosphatase activity in the culture medium. The toxic effect of olanzapine was less pronounced in comparison to haloperidol. According to the data from literature, AP upregulate the expression of lipogenesis genes in the cells of central nervous system, adipose tissue and liver, that might lead to hyperlipidemia. However, we observe in our experiments no increase in the levels of total cholesterol, of cholesterol in lipoproteins of high and low density, of triglycerides in the culture medium containing haloperidol or olanzapine. That observation may have been due to the fact that both AP, which are cationic amphiphiles, are capable to inhibit intracellular traffic of lipids. We also found no effects of haloperidol and olanzapine on the activity of aspartate aminotransferase and gamma-glutamyltransferase, while both AP did reduce the alanine aminotransferase activity. Our work proves that HepG2 cells can be helpful as an in vitro model to obtain new data on metabolic effects of drugs on the cells of hepatic origin and to assess the risk of a drug hepatotoxicity in preclinical studies.

[Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms].

"Typical" antipsychotics remain the wide-prescribed drugs in modern psychiatry. But these drugs are associated with development of extrapyramidal symptoms (EPS). Preventive methods of EPS are actively developed and they concentrate on personalized approach. The method of taking into account genetic characteristics of patient for prescribing of treatment was proven as effective in cardiology, oncology, HIV-medicine. In this review the modern state of pharmacogenetic research of antipsychotic-induced EPS are considered. There are pharmacokinetic and pharmacodynamic factors which impact on adverse effects. Pharmacokinetic factors are the most well-studied to date, these include genetic polymorphisms of genes of cytochrome P450. However, evidence base while does not allow to do the significant prognosis of development of EPS based on genetic testing of CYP2D6 and CYP7A2 polymorphisms. Genes of pharmacodynamics factors, which realize the EPS during antipsychotic treatment, are the wide field for research. In separate part of review research of such systems as dopaminergic, serotonergic, adrenergic, glutamatergic, GABAergic, BDNF were analyzed. The role of oxidative stress factors in the pathogenesis of antipsychotic-induced EPS was enough detailed considered. The system of those factors may be used for personalized risk assessment of antipsychotics' safety in the future. Although there were numerous studies, the pharmacogenetic-based prevention of EPS before prescribing of antipsychotics was not introduced. However, it is possible to distinguish the most perspectives markers for further research. Furthermore, brief review of new candidate genes provides here, but only preliminary results were published. The main problem of the field is the lack of high- quality studies. Moreover, the several results were not replicated in repeat studies. The pharmacogenetic-based research must be standardized by ethnicity of patients. But there is the ethnical misbalance in world literature. These facts explain why the introduction of pharmacogenetic testing for risk assessment of antipsychotic-induced EPS is so difficult to achieve.