We investigated whether protein kinase Cδ (PKCδ) mediates cocaine-induced hepatotoxicity in mice. Cocaine treatment (60 mg/kg, i.p.) significantly increased cleaved PKCδ expression in the liver of wild-type (WT) mice, and led to significant increases in oxidative parameters (i.e., reactive oxygen species, 4-hydroxylnonenal and protein carbonyl). These cocaine-induced oxidative burdens were attenuated by pharmacological (i.e., rottlerin) or genetic depletion of PKCδ. We also demonstrated that treatment with cocaine resulted in significant increases in nuclear factor erythroid-2-related factor 2 (Nrf-2) nuclear translocation and increased Nrf-2 DNA-binding activity in wild-type (WT) mice. These increases were more pronounced in the rottlerin-treated WT or PKCδ knockout mice than in the saline-treated WT mice. Although cocaine treatment increased Nrf-2 nuclear translocation, DNA binding activity, and γ-glutamyl cysteine ligases (i.e., GCLc and GCLm) mRNA expressions, while it reduced the glutathione level and GSH/GSSG ratio. These decreases were attenuated by PKCδ depletion. Cocaine treatment significantly increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of WT mice signifying the hepatic damage. These increases were also attenuated by PKCδ depletion. In addition, cocaine-induced hepatic degeneration in WT mice was evident 1 d post-cocaine. At that time, cocaine treatment decreased Bcl-2 and Bcl-xL levels, and increased Bax, cytosolic cytochrome c, and cleaved caspase-3 levels. Pharmacological or genetic depletion of PKCδ significantly ameliorated the pro-apoptotic properties and hepatic degeneration. Therefore, our results suggest that inhibition of PKCδ, as well as activation of Nrf-2, is important for protecting against hepatotoxicity induced by cocaine.

我们调查了蛋白激酶Cδ（PKCδ）是否介导可卡因诱导的小鼠肝毒性。可卡因治疗（60 mg / kg，腹腔注射）可显着增加野生型（WT）小鼠肝脏中PKCδ的裂解表达，并导致氧化参数（即活性氧，4-羟基壬醛和羰基蛋白）的显着增加。这些可卡因诱导的氧化负荷通过药理学（即rottlerin）或PKCδ的遗传耗竭而减弱。我们还证明，在野生型（WT）小鼠中，可卡因治疗可导致核因子红系2相关因子2（Nrf-2）核转运显着增加，并增加Nrf-2 DNA结合活性。这些增加在用rottlerin处理的WT或PKCδ基因敲除小鼠中比在用盐水处理的WT小鼠中更为明显。尽管可卡因治疗增加了Nrf-2核易位，DNA结合活性和γ-谷氨酰半胱氨酸连接酶（即GCLc和GCLm）mRNA的表达，但同时降低了谷胱甘肽水平和GSH / GSSG比。这些减少由于PKCδ耗尽而减弱。可卡因治疗可显着提高野生型小鼠血清中丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）的水平，表明肝损伤。这些增加也因PKCδ耗尽而减弱。此外，可卡因诱导的WT小鼠肝变性在可卡因后1 d是明显的。当时，可卡因治疗降低了Bcl-2和Bcl-xL的水平，并增加了Bax，胞质细胞色素c和caspase-3的裂解水平。药理学或遗传学上的PKCδ耗竭显着改善了促凋亡特性和肝变性。