Assessment of the genotoxicity and pro-oxidative potentials of risperidone in L929 murine fibroblasts

Risperidone is an atypical antipsychotic drug clinically used to treat mood disorders, autism, and schizophrenia. Since risperidone is typically prescribed chronically for clinical use, it is important to determine potential side effects, such as toxicogenic consequences, which remain under-explored for this class of drugs. The main goal of this study was to (1) examine the genotoxicity attributed to risperidone using L929 murine fibroblasts with different standardized techniques (MTT, comet, and micronucleus (MN) assays) and (2) and oxidative potential by measuring levels of reduced glutathione (GSH) and carbonyl proteins, oxidative indices. Data demonstrated that risperidone exhibited a cytotoxic effect after 24 hr exposure, reducing cell viability by approximately 23% (compared to negative controls) at the highest concentration (500 µM). Standard alkaline comet (pH > 13) and MN assays noted the absence of genotoxic/mutagenic potentials after treatment with risperidone (100 and 500 µM), even in the presence of an exogenous metabolizing source (S9 fraction). However, the comet assay displayed the presence of the enzyme formamidopyrimidine DNA-glycosylase (FPG) in cells exposed to 500 µM risperidone resulting in a significant increase in levels of DNA damage, indicative of oxidative damage to the genome. This oxidative DNA damage was corroborated by reduction of the glutathione (GSH) levels, through modulation of GSH-dependent enzymes, and elevated levels of protein oxidation in cultures exposed to 500 µM risperidone. Data demonstrated that 500 µM risperidone exerted a cytotoxic effect on L929 cells accompanied by induction of DNA strand breaks generation of oxidative stress.