Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice

Abstract

Background & Aims Oltipraz (4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione), a promising cancer preventive agent, has an anti-oxidative activity and ability to enhance glutathione biosynthesis, phase II detoxification enzymes and multidrug resistance-associated protein-mediated efflux transporters. Oltipraz can protect against hepatotoxicity caused by carbon tetrachloride, acetaminophen and alpha-naphthylisothiocyanate. Whether oltipraz has hepato-protective effects on obstructive cholestasis is unknown. Methods We administered oltipraz to mice for 5 days prior to bile duct ligation (BDL) for 3 days. Liver histology, liver function markers, bile flow rates and hepatic expression of profibrogenic genes were evaluated. Results Mice pretreated with oltipraz prior to BDL demonstrated higher levels of serum aminotransferases and more severe liver damage than in control mice. Higher bile flow and glutathione secretion rates were observed in unoperated mice treated with oltipraz than in control mice, suggesting that liver necrosis in oltipraz-treated BDL mice may be related partially to increased bile-acid independent flow and biliary pressure. Oltipraz treatment in BDL mice enhanced -smooth muscle actin expression, consistent with activation of hepatic stellate cells and portal fibroblasts. Matrix metalloproteinases (MMP) 9 and 13 and tissue inhibitors of metalloproteinases (TIMP) 1 and 2 levels were increased in the oltipraz -treated BDL group, suggesting that the secondary phase of liver injury induced by oltipraz might be due to excessive MMP and TIMP secretions which induce remodeling of the extracellular matrix. Conclusions Oltipraz treatment exacerbates the severity of liver injury following BDL and should be avoided as therapy for extrahepatic cholestatic disorders due to bile duct obstruction.

Lobe-Specific Heterogeneity in Asymmetric Dimethylarginine and Matrix Metalloproteinase Levels in a Rat Model of Obstructive Cholestasis

“…Recent works support the crucial role of the analysis of the MMPs activation not only after 1-2 weeks after BDL but also after few days of occlusion [36, 37]. We confirm in rats the previous results in mice because we also observed an increase in MMP-2 and MMP-9 that in our conditions occurs significantly in RL than in ML and LL.…”

Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism

“…Moreover, recent studies have shown that the NRF2 activators such as UDCA and oltipraz induced MRP efflux transporters in rodent liver (Eba et al, 2013;Okada et al, 2008;Weerachayaphorn et al, 2014), and NRF2 binds to AREs at -9919 bp in the mouse MRP3 gene and to AREs/antioxidant response-like elements a t -3753 to -3767 bp in the mouse MRP4 gene (Maher et al, 2007). In this study, BDL caused intrinsic activation of NRF2 in mice as an adaptive response, however, this adaption was not potent in fully preventing cholestatic liver injury as demonstrated by marked liver pathological alteration and upregulation of multiple serum and liver biochemicals.…”

Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice

“…Here, a reduction of obesity and hepatic lipids and an improvement of glucose tolerance were observed in rodent models [6–8]. However, these molecules are associated with toxic effects, which could have been a considerable confounding factor in the metabolic studies [9, 10]. Genetic models leading to either a loss-of- or gain-of-Nrf2 function gave no clear picture about the role of Nrf2 in hepatic lipid and carbohydrate metabolism [11–20].…”