<b>1</b><i><b>O</b></i><b>, 20</b><i><b>O</b></i><b>-diacetyl kamebakaurin protects against acetaminophen-induced hepatotoxicity in </b><b>mice </b>

Abstract

The present study aimed to investigate the protective effects of kamebakaurin (KA) and 1O, 20O-diacetyl kamebakaurin (Ac 2 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, Ac 2 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 Ac 2 KA significantly attenuated APAP-induced hepatic injury. The protective effect of Ac 2 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. Ac 2 KA also decreased APAP-induced RIP-1 activation and nuclear factor kappa B (NF-κB) p65 translocation. Moreover, Ac 2 KA repressed mRNA expression of Cyp1a2/2e1 in the liver. Our results showed that KA and Ac 2 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 Ac 2 KA included those of KA, as well as RIP-1 inactivation, NF-κB inhibition, and Cyp inhibition.

Biofabrication of Hepatic Constructs by 3D Bioprinting of a Cell‐Laden Thermogel: An Effective Tool to Assess Drug‐Induced Hepatotoxic Response

“…[ 52 ] It represents about 13% of CYP enzymes in the human liver, and is involved, among others, in APAP metabolism. [ 56–58 ]…”

Protection from acetaminophen-induced hepatotoxicity by post-administration of 1<i>O</i>, 20<i>O</i>-diacetyl kamebakaurin in mice

“…Recently, this inhibitor has been implicated in playing a role related to APAP-induced hepatotoxicity (Henderson et al, 2007;Schwabe et al, 2003). Since our previous analysis showed that APAP-induced c-Jun N-terminal kinase phosphorylation is attenuated by Ac 2 KA (Yoshioka et al, 2018), this hypothesis is plausible. Saito et al showed that NAC post-administration has two effects: enhancing hepatic glutathione levels and support- (n = 5-7 per group).…”

“…Our previous investigation indicated that 1O, 20Odiacetyl kamebakaurin (Ac 2 KA), which is synthesized from kamebakaurin, prevents APAP-induced hepatic injury by inhibiting lipid peroxidation and inflammatory responses (Yoshioka et al, 2018). Although Ac 2 KA was found to exert a good protective effect, our previous study only evaluated the pre-treatment effects of Ac 2 KA.…”

Evaluation of the protective effect of losartan in acetaminophen-induced liver and kidney damage in mice

“…Losartan administration caused an improvement in serum TAS, GSH, TOS, GSSG, and MDA levels depending on the dose. In studies evaluating the protective efficacy of Tinospora cordifolia and Boerhavia diffusa extracts, irbesartan, n-acetylcysteine, and taurine in hepatotoxicity induced by acetaminophen; it has been shown that these test substances cause an increase in GSH and TAS levels after acetaminophen injection and a decrease in TOS, GSSG, and MDA levels (Acharya and Lau-Cam 2010 ; Kaushik et al 2017b ; Yoshioka et al 2018 ; Helal and Samra 2020 ). The improvement in TAS, GSH, TOS, GSSG, and MDA levels, which are oxidative stress markers, can be considered an indication that losartan has a protective and curative effect by reducing oxidative stress in hepatotoxicity induced by acetaminophen.…”