Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

Abstract

Aim: α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats. Methods: SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6, and ATP content, as well as the expression of liver transporter genes and proteins were assayed. Results: ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL, and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO 3 -. ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR, and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANITinduced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective. Conclusion: Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

“…The modulation of pro-inflammatory responses plays a critical role in cholestatic liver injury [33] . The present study demonstrated that hepatic MPO activity was significantly increased after ANIT exposure, which is consistent with results from a previous study [34] . However, oral sweroside administration alleviated the increase in hepatic MPO activity after ANIT treatment, which contributed to the inhibition of neutrophil infiltration into liver tissues.…”

“…Previous reports have demonstrated that bile acid synthesis may be inhibited during liver damage [33,34] . The present study demonstrated that sweroside significantly attenuated the down-regulation of Cyp7a1, Cyp8b1, and Hsd3b7, which is consistent with results from previous reports [14,17] .…”

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

“…Nrf2 can regulate the expression and activation of variety of enzymes that counteract oxidative stress and promote cell survival [30,31]. In addition, studies have shown that the activation of Nrf2 can safeguard against cholestasis caused by bile duct ligation and alphanaphthyl isocyanate models via the induction of many anti-oxidative genes [5,32,33].…”

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

“…Our data may provide an alternative explanation for this observation: the protective role of TER may arise from its inhibition of NTCP function, which leads to less bile acid accumulation in hepatocytes and less apoptosis. However, from another perspective, down-regulation of NTCP and disturbance of bile acid circulation may lead to liver toxicity over the long term [32][33][34] . In fact, the elimination half-life of TER is approximately 2 weeks, which is thought to result from a combination of extremely low hepatic clearance and enterohepatic recycling [27,35] .…”