Use of HepG2 cell line for evaluation of toxic and metabolic antipsychotic action

Аннотация

The toxic and metabolic effects of antipsychotics on cells of hepatic origin have been studied in vitro using human hepatoblastoma cell line HepG2. The cells were cultured in the presence of two first- and second-generation antipsychotics, haloperidol and olanzapine, respectively, at concentrations that can exist in the blood, liver and other tissues with high lipid content when the drugs are used for therapeutic purposes. During cultivation in several periods, the products of carbohydrate and lipid metabolism were quantified, the activities of several enzymes in the culture medium were measured, and viability (proliferation) of cells was assessed with MTS assay. Both drugs were toxic to HepG2 cells, which was manifested in inhibition of proliferation and an increased alkaline phosphatase activity in the culture medium. The toxic action of olanzapine in the doses used was less significant than that of haloperidol. According to literature data, antipsychotics increase the expression of lipogenesis genes in cells of the central nervous system, adipose tissue and liver, which can lead to hyperlipidemia. However, we have not observed increased levels of total cholesterol, cholesterol of low and high density lipoproteins, and triglycerides in the culture medium of HepG2 cells in the presence of haloperidol and olanzapine. This may be associated with the fact that both drugs, which are cationic amphiphiles, are able to inhibit intracellular lipid trafficking. Moreover, both drugs had no effect on the activity of aspartate aminotransferase and gamma-glutamyltransferase in the culture medium, but contributed to a decrease in the activity of alanine aminotransferase. Overall, our work has confirmed that HepG2 cells may serve as a useful model to obtain new data on drug effects on the metabolism of cells of hepatic origin and to assess the risk of hepatotoxicity in preclinical studies.