Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1.
The present study was carried out to investigate whether taurine plays any beneficial role in acetaminophen (APAP)-induced acute hepatotoxicity. APAP exposure increased the plasma levels of ALT, ALP, LDH, TNF-alpha and NO production. Moreover, APAP treatment reduced the glutathione level and antioxidant enzyme activities, increased lipid peroxidation and caused hepatic DNA fragmentation which ultimately leads to cellular necrosis. Also, incubation of hepatocytes with APAP reduced cell viability, enhanced ROS generation and increased CYP2E1 activity. APAP overdose caused injury in the hepatic tissue and hepatocytes via the upregulation of CYP2E1 and JNK. Taurine treatment was effective in counteracting APAP-induced hepatic damages, oxidative stress and cellular necrosis. Results indicate that APAP overdose caused hepatic injury due to its metabolism to hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), usually catalysed by CYP2E1, and via the direct activation of JNK-dependent cell death pathway. Taurine possesses prophylactic as well as therapeutic potentials against APAP-induced hepatic injury.
Das
Joydeep
J
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054, India.
Ghosh
Jyotirmoy
J
Manna
Prasenjit
P
Sil
Parames C
PC
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002469:Cell Separation; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015151:Immunoblotting; D015227:Lipid Peroxidation / Q000187:drug effects; D017093:Liver Failure / Q000139:chemically induced* / Q000517:prevention & control; D048670:MAP Kinase Kinase 4 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013654:Taurine / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D017382:Reactive Oxygen Species; D013654:Taurine; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D048670:MAP Kinase Kinase 4