Effects of combined toxicity of methamphetamine and ketamine on apoptosis, oxidative stress and genotoxicity in HepG2 cells

Methamphetamine (MA) and ketamine (KET) are widely abused drugs individually. Previous surveys have revealed that the combined consumption of MA and KET were prevalent in illicit drugs abusers. However, few studies on the toxic effects induced by the combination of MA and KET have been reported. In this study, combined treatments were carried out using 3 x 3 full factorial design to determine the combined effects of MA and KET on apoptosis, oxidative stress and genotoxicity in HepG2 cells. Higher apoptosis and oxidative damage were observed in the MA treatments groups. Compared with control groups, the maximum apoptotic rate and level of malondialdehyde were similar to 7.7 fold and similar to 5.5 fold respectively. The mechanism that excessive oxidative stress resulted in cell apoptosis and DNA damage was inferred. For the joint effects, synergistic or additive interactions were found at different biological endpoints for various combinations, likely due to the mechanism in which MA promotes the metabolism of KET, which together provokes even greater oxidative stress. In conclusion, synergistic or additive interactions between MA and KET enhance cytotoxicity, oxidative damage and genotoxicity in HepG2 cells more than either of the drugs alone, which implies higher risk for abusers when exposed to the polydrug situation.