Prophylactic Effect of Resveratrol Against Ethinylestradiol-Induced Liver Cholestasis

Abstract

Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. The aim of the present article was to investigate anticholestatic activity of resveratrol (RES) against liver cholestasis induced by EE in adult female rats. The daily oral administration of the RES at a concentration of 25 mg/kg body weight for 15 days to rats treated with EE (100 μg/kg body weight for 5 days) resulted in a significant protection against EE-induced decrease in both serum cholesterol and bile acid levels as well as against an increase of serum bilirubin concentration. The treatment also resulted in a significant increase in hepatic superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase activities as well as hepatic protein-bound and nonprotein sulfhydryl groups. RES inhibited serum alkaline phosphatase, alanine aminotransferase, pi-glutathione-S-transferase, gamma-glutamyl transpeptidase, and alpha-glutathione-S-transferase activities, as well as reduced serum tumor necrosis factor-alpha, nitric oxide, and hepatic malondialdehyde as compared to EE-treated rats. The results clearly suggest that RES has a powerful prophylactic action in cholestasis induced by EE. Taken together, RES has potential as a preventive and therapeutic agent for cholestasis and deserves clinical trial in the near future as an adjuvant therapy in women treated with estrogen.

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“…The reductions of hepatic SOD and CAT activities in EE-induced cholestasis rats as compared with normal rats were reported in this study due to production of NO; as a result of inflammation and destructive processes 4,60 , the oxidative stress on the hepatic cells was increased leading to depletion of antioxidant enzymes that scavenge the toxic superoxide and hydrogen peroxide radicals that promote lipid peroxidation, whereas the ferulic acid-treated groups showed a significant increase in the hepatic SOD, GPx, CAT and GSH levels of the EE-induced cholestatic rats ( Table 3). It was reported that the in-vitro and an in-vivo antioxidant property of ferulic acid probably arises from its ability to protect against the molecular effects of lipid peroxidation, free radicals, and ROS, and it also delays the progress of many chronic diseases 18,[21][22][23] .…”

“…had significant reductions in plasma cholesterol and total bile acid (TBA) as well as elevations of biochemical markers ALT, AST, ALP, LDH, GGT, total bilirubin and direct bilirubin (Tables 1 and 2). Liver cholestasis is associated with cellular necrosis and increases in tissue lipid peroxidation resulting in oxidative stress and ALT, ALP, p-GST, γ -GT, α-GST, and bilirubin were elevated 4 . Cholestatic activity of EE appears to act through reduction of biliary excretory activity of the canalicular membrane 47 and decreased elimination of conjugated bilirubin and an increase in the conjugated level in plasma, a symptom diagnostic for obstructive jaundice 48 .…”

“…showed significant protection against induced decrease in serum cholesterol and bile acids through inhibiting squalene monooxygenase, a rate-limiting enzyme in cholesterol biosynthesis. Also, ferulic acid stimulates cholesterol-7-α-hydroxylase activity, which is responsible for bile acids synthesis and reduces liver cholesterol levels 4,53 .…”

Mitigating Effect of Resveratrol on the Structural Changes of Mice Liver and Kidney Induced by Cadmium; A Stereological Study

“…Up to now, different beneficial effects of RES have been reported, including anticancer and neuroprotective properties and cardiovascular protection. This substance functions as an antioxidant and anti-inflammatory mediator and changes the pro-inflammatory cytokines in rats' hepatocytes (13)(14)(15)(16). RES is known to be associated with grapes, mulberries, groundnuts, and peanuts.…”

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

“…Recently, it was found that resveratrol improved cholestatic liver injury by decreasing fibrosis and promoting hepatocyte regeneration [12] , decreasing oxidative damage [13] , and modulating apoptosis, mitochondrial biogenesis and autophagy [14] . The current evidence for the protective effect of resveratrol on cholestasis was mainly obtained from studies using bile duct ligation (an extrahepatic model) in animals.…”