RRC ID 54374
Author Mai HN, Sharma G, Sharma N, Shin EJ, Kim DJ, Pham DT, Trinh QD, Jang CG, Nah SY, Jeong JH, Kim HC.
Title Genetic depletion of p53 attenuates cocaine-induced hepatotoxicity in mice.
Journal Biochimie
Abstract Cocaine, an addictive drug, is known to induce hepatotoxicity via oxidative damage and proapoptosis. Since p53, a tumor suppressor gene, plays a major role in inducing oxidative stress and apoptosis, we examined the role of p53 inhibition against cocaine-induced hepatotoxicity. Cocaine treatment significantly increased oxidative parameters (i.e., reactive oxygen species, 4-hydroxylnonenal, and protein carbonyl) in the liver of wild type (WT) mice. We found that the pharmacological (i.e. pifithrin-α) and genetic (i.e. p53 knockout) inhibition of p53 significantly attenuates cocaine-induced hepatotoxicity. Cocaine treatment increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of mice, signifying hepatic damage. Consistently, these increases were attenuated by inhibition of p53, implying protection against cocaine-induced hepatic damage. In addition, cocaine treatment significantly increased PKCδ, cleaved PKCδ and p53 levels in the liver of WT mice. These increases were followed by the interaction between p53 and PKCδ, and pro-apoptotic consequences (i.e., cytosolic release of cytochrome c, activation of caspase-3, increase in Bax level and decreases in Bcl-2 and Bcl-xL levels). These changes were attenuated by p53 depletion, reflecting that the critical role of PKCδ in p53-mediated apoptotic potentials. Combined, our results suggest that the inhibition of p53 is important for protection against oxidative burdens, pro-apoptotic events, and hepatic degeneration induced by cocaine.
Volume 158
Pages 53-61
Published 2019-3-1
DOI 10.1016/j.biochi.2018.12.009
PII S0300-9084(18)30354-7
PMID 30576773
MeSH Alanine Transaminase / blood Alanine Transaminase / genetics Animals Apoptosis / drug effects* Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism Aspartate Aminotransferases / blood Aspartate Aminotransferases / genetics Chemical and Drug Induced Liver Injury / genetics Chemical and Drug Induced Liver Injury / metabolism* Chemical and Drug Induced Liver Injury / pathology Cocaine / toxicity* Liver / metabolism* Liver / pathology Male Mice Mice, Knockout Oxidative Stress / drug effects* Oxidative Stress / genetics Protein Kinase C-delta / genetics Protein Kinase C-delta / metabolism Tumor Suppressor Protein p53 / deficiency*
IF 3.413
Times Cited 1
Mice RBRC01361