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Protective potential of glutathione peroxidase‐1 gene against cocaine‐induced acute hepatotoxic consequences in mice
Author(s) -
Mai Huynh Nhu,
Jung Tae Woo,
Kim DaeJoong,
Sharma Garima,
Sharma Naveen,
Shin EunJoo,
Jang ChoonGon,
Nah SeungYeol,
Lee Sung Hoon,
Chung Yoon Hee,
Lei Xin Gen,
Jeong Ji Hoon,
Kim HyoungChun
Publication year - 2018
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3666
Subject(s) - oxidative stress , glutathione peroxidase , reactive oxygen species , chemistry , pharmacology , lipid peroxidation , glutathione , mitochondrion , sod2 , cytosol , sod1 , protein kinase c , superoxide dismutase , biochemistry , endocrinology , biology , kinase , enzyme
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 1 hour, with a maximum level at 6 hours 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 Ca 2+ , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C δ (PKC δ), mitochondrial translocation of PKC δ, 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 δ.