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1O, 20O-diacetyl kamebakaurin protects against acetaminophen-induced hepatotoxicity in mice

Hiroki Yoshioka, Tsunemasa Nonogaki, Hiroyuki Ohnishi, Nobuyuki Fukuishi, Masae Yoshikawa, Ming-Yu Gui, Yong-Ri Jin, Xu-Wen Li, Yoshiyuki Adachi, Naohito Ohno, Koichi Takeya, Yukio Hitotsuyanagi, Nobuhiko Miura, Yutaka Aoyagi
Biomedical Research 2018, 39 (5): 251-260
The present study aimed to investigate the protective effects of kamebakaurin (KA) and 1O, 20O-diacetyl kamebakaurin (Ac2 KA) on acetaminophen (APAP)-induced hepatotoxicity and compare the hepatoprotective mechanisms of the two chemicals. Seven-week-old male C57BL/6J mice were orally administered KA, Ac2 KA, or an ethanol/olive oil emulsion once per day for 7-days. Twenty-four hours after the final administration, the mice were fasted and then intraperitoneally injected with 450 mg/kg APAP or saline. At 16 h after injection, the mice were euthanized and blood samples were collected for plasma analysis. Pretreatment with KA and Ac2 KA significantly attenuated APAP-induced hepatic injury. The protective effect of Ac2 KA was stronger than that of KA. These two chemicals attenuated oxidative stress, inflammatory cytokine production, c-jun N-terminal kinase activation, and receptor-interacting protein (RIP)-3 activation. Ac2 KA also decreased APAP-induced RIP-1 activation and nuclear factor kappa B (NF-κB) p65 translocation. Moreover, Ac2 KA repressed mRNA expression of Cyp1a2/2e1 in the liver. Our results showed that KA and Ac2 KA exerted protective effects against APAP-induced hepatotoxicity. The responsible mechanisms may be related to the chemicals' antioxidant activity and the inhibition of c-jun N-terminal kinase activation and RIP-3 activation. The effects of Ac2 KA included those of KA, as well as RIP-1 inactivation, NF-κB inhibition, and Cyp inhibition.


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