Protein kinase Cδ knockout mice are protected from cocaine-induced hepatotoxicity

Publication date: Available online 25 October 2018Source: Chemico-Biological InteractionsAuthor(s): Huynh Nhu Mai, Sung Hoon Lee, Garima Sharma, Dae-Joong Kim, Naveen Sharma, Eun-Joo Shin, Duc Toan Pham, Quynh Dieu Trinh, Choon-Gon Jang, Seung-Yeol Nah, Ji Hoon Jeong, Hyoung-Chun KimAbstractWe 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) ...

Source: Chemico Biological Interactions - October 25, 2018 Category: Biochemistry Source Type: research