Methamphetamine induces hepatotoxicity via inhibiting cell division, arresting cell cycle and activating apoptosis: In vivo and in vitro studies

- Methamphetamine (METH) induced obvious acute hepatic injury in rats.
- Genes of cell cycle and activator of apoptosis were markedly regulated by microarray.
- Levels of these genes/proteins were verified by RT-qPCR/western blotting in rats.
- Cell cycle arrest induced by METH was confirmed in Brl-3A cells by flow cytometry.
- Activation of apoptosis took an important role in METH-induced hepatotoxicity.

Methamphetamine (METH) resulted in acute hepatic injury. However, the underlying mechanisms have not been fully clarified. In the present study, rats were treated with METH (15 mg/kg B.W.) for 8 injections (i.p.), and the levels of alanine transaminase, asparatate transaminase and ammonia in serum were significantly elevated over those in the control group, suggesting hepatic injury, which was evidenced by histopathological observation. Analysis of the liver tissues with microarray revealed differential expressions of a total of 332 genes in METH-treated rats. According to the GO and KEGG annotations, a large number of down-regulated cell cycle genes were screened out, suggesting that METH induced cell cycle arrest and deficient of cell cycle checkpoint. Related genes and proteins were confirmed by RT-qPCR and western blotting in rat livers, respectively. Moreover, treatment of Brl-3A cells with METH caused significant cytotoxic response and marked cell cycle arrest. Furthermore, overexpressions of Cidea, cleaved caspase 3 and PARP 1 in METH-treated rats indicated activation of apoptosis, while its inhibition alleviated cell death in Brl-3A cells, suggesting that activation of apoptosis took an important role in METH-induced hepatotoxicity. Taken together, the present study demonstrates that METH induced hepatotoxicity via inducing cell cycle arrest and activating apoptosis.