Methamphetamine induces hepatotoxicity via inhibiting cell division, arresting cell cycle and activating apoptosis: In vivo and in vitro studies.
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.
Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
Qi
Q
Wang
Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
Li-Wen
LW
Wei
Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, No. 600 Tianhe Road, 510630 Guangzhou, China.
Huan-Qin
HQ
Xiao
Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
Ye
Y
Xue
Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
Si-Hao
SH
Du
Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China. Electronic address: yungliu@126.com.
Yun-Gang
YG
Liu
Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China. Electronic address: xiexiaoli1999@126.com.
Xiao-Li
XL
Xie
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008694:Methamphetamine
Apoptosis; Cell cycle arrest; Hepatotoxicity; METH; Microarray