Yoshioka Hiroki, Nonogaki Tsunemasa, Ohnishi Hiroyuki, Fukuishi Nobuyuki, Yoshikawa Masae, Gui Ming-Yu, Jin Yong-Ri, Li Xu-Wen, Adachi Yoshiyuki, Ohno Naohito, Takeya Koichi, Hitotsuyanagi Yukio, Miura Nobuhiko, Aoyagi Yutaka
College of Pharmacy, Kinjo Gakuin University.
Department of Health Science, School of Allied Health Science and Graduate School of Medical Sciences, Kitasato University.
Biomed Res. 2018;39(5):251-260. doi: 10.2220/biomedres.39.251.
The present study aimed to investigate the protective effects of kamebakaurin (KA) and 1O, 20O-diacetyl kamebakaurin (AcKA) 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, AcKA, 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 AcKA significantly attenuated APAP-induced hepatic injury. The protective effect of AcKA 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. AcKA also decreased APAP-induced RIP-1 activation and nuclear factor kappa B (NF-κB) p65 translocation. Moreover, AcKA repressed mRNA expression of Cyp1a2/2e1 in the liver. Our results showed that KA and AcKA 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 AcKA included those of KA, as well as RIP-1 inactivation, NF-κB inhibition, and Cyp inhibition.
本研究旨在探讨甘茶素（KA）和1O, 20O - 二乙酰甘茶素（AcKA）对乙酰氨基酚（APAP）诱导的肝毒性的保护作用，并比较这两种化合物的肝保护机制。7周龄雄性C57BL/6J小鼠每天口服一次KA、AcKA或乙醇/橄榄油乳剂，连续7天。末次给药24小时后，小鼠禁食，然后腹腔注射450 mg/kg APAP或生理盐水。注射后16小时，处死小鼠并采集血样进行血浆分析。KA和AcKA预处理显著减轻了APAP诱导的肝损伤。AcKA的保护作用强于KA。这两种化合物减轻了氧化应激、炎性细胞因子产生、c - jun N末端激酶激活和受体相互作用蛋白（RIP）- 3激活。AcKA还降低了APAP诱导的RIP - 1激活和核因子κB（NF - κB）p65易位。此外，AcKA抑制了肝脏中Cyp1a2/2e1的mRNA表达。我们的结果表明，KA和AcKA对APAP诱导的肝毒性具有保护作用。其作用机制可能与化合物的抗氧化活性以及对c - jun N末端激酶激活和RIP - 3激活的抑制有关。AcKA的作用包括KA的作用，以及RIP - 1失活、NF - κB抑制和Cyp抑制。
