期刊
JOURNAL OF APPLIED TOXICOLOGY
卷 38, 期 12, 页码 1502-1520出版社
WILEY
DOI: 10.1002/jat.3666
关键词
cocaine; glutathione peroxidase-1 gene; hepatotoxicity; mitochondria; oxidative stress; pro-apoptosis
类别
资金
- National Research Foundation of Korea
- Korea Food and Drug Administration [14182MFDS979]
Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1hour, with a maximum level at 6hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca2+, while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C (PKC), mitochondrial translocation of PKC, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKC.
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