Wednesday , 29 March 2017

Efficacy of PARP1 inhibitor nutlin3a on liver injury induced by Ischemia-reperfusion

Daisuke Kawahara1, Kosho Yamanouchi 1, Naoyuki Okita2, Tamotsu Kuroki1, Yoshikazu Higami2 and Susumu Eguchi1
1Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
2Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan

Nutlin 3a was known to have effects of stabilization of p53 and degradation of Poly (ADP-ribose) polymerase 1 (PARP1) in cell-specific manner.  This implied that the reagent potentially would alleviate hepatic ischemia reperfusion (I/R) injury.  First, to evaluate an efficacy of nutlin3a in normal liver, we administered it to male C57Bl/6 mice intraperitoneally at doses of 0 (vehicle only), 5, 20, and 100 mg/kg of body-weight.  The animals were killed at 4, 8, and 12 hours after administration and proteins of p53 and PARP1 in the liver were evaluated.  As results, no changes were observed in proteins of p53 and PARP1 in both the normal and I/R liver by administration of nutlin3a.  Next, we assessed the effects of nutlin3a on the liver after I/R.  Twenty-four hours after administration of nutlin3a, the mice suffered from hepatic ischemia, and then were sacrificed at 8 and 24 hours after reperfusion.  Nutilin3a did not only show the effect of alleviation of hepatic I/R injury, but also seemed to have cytotoxicity to hepatocyte in dose-dependent manner. In conclusion, a protective effect of nutilin3a on hepatic I/R was not evident in our model. To elucidate definitive effects of nutlin3a in the liver, in vitro study on cell-selectiveness would be needed.
Keywords: PARP1, liver, ischemia-reperfusion

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