Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation.
Acute exposure of acetaminophen (APAP), a widely used analgesic and antipyretic drug, causes severe renal damage and no specific agent has been reported so far that plays any beneficial role in this organ pathophysiology. In the present study, the protective role of taurine on APAP-induced nephrotoxicity was investigated in mice. In order to induce acute nephrotoxicity, APAP was administered at a single dose of 2g/kg body weight orally to male adult albino mice of Swiss strain. APAP exposure for 24h significantly increased plasma level of blood urea nitrogen (BUN), creatinine, uric acid, TNF-alpha, NO production, urinary gamma-glutamyl transpeptidase (gamma-GT) activity, total urinary protein and urinary glucose level accompanied by a decrease in Na(+)-K(+)-ATPase activity. Moreover, APAP administration significantly increased MDA, protein carbonylation, GSSG level, intracellular ROS production and cytochrome P450 enzyme (CYPP450) activity. The same exposure decreased GSH level, ferric reducing/antioxidant power (FRAP) as well as the activities of antioxidant enzymes indicating that APAP-induced renal damage was mediated through oxidative stress. Besides, APAP exposure significantly reduced mitochondrial membrane potential and induced up-regulation of CYP2E1 in renal tissues although JNK did not play any significant role in this APAP-induced renal pathophysiology. Caspase 9/3 immunoblot and DNA fragmentation analyses showed that APAP-induced renal cell damage was mostly necrotic in nature, although some apoptosis also occurred simultaneously. Taurine treatment both pre and post (150 mg/kg body weight for 3 days, orally) to APAP exposure, however, significantly reduced APAP-induced nephrotoxicity through its antioxidant properties, urinary excretion of APAP and suppression of CYP2E1. Results suggest that taurine might be a potential therapeutic candidate against APAP-induced acute nephrotoxicity.
Das
Joydeep
J
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India.
Ghosh
Jyotirmoy
J
Manna
Prasenjit
P
Sil
Parames C
PC
D000082:Acetaminophen / Q000633:toxicity* / Q000652:urine*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D020011:Protective Agents / Q000494:pharmacology; D013654:Taurine / Q000494:pharmacology*
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D020011:Protective Agents; D013654:Taurine; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1