Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox. Issue 3 (March 2015)

• Record Type: Journal Article
• Authors: Sobbe, Amy; Bridle, Kim R; Jaskowski, Lesley; de Guzman, C Erika; Santrampurwala, Nishreen; Clouston, Andrew D; Campbell, Catherine M; Subramaniam, V Nathan; Crawford, Darrell H G
• Is Part Of: Journal of gastroenterology and hepatology. Volume 30:Issue 3(2015:Mar.)
• Page Start: 638
• Page End: 645
• Publication Date: 2015-03
• Subjects: Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; Liver -- Diseases -- Periodicals; Gastroenterology -- Periodicals; Liver Diseases -- Periodicals; 616.33
• DOI: 10.1111/jgh.12720
• Languages: English
• ISSNs: 0815-9319

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jgh12720-sec-0001" sec-type="section"> <title>Background and Aim</title> <p>Development of effective antifibrotic treatments that can be translated to clinical practice is an important challenge in contemporary hepatology. A recent report on β‐thalassemia patients demonstrated that deferasirox treatment reversed or stabilized liver fibrosis independent of its iron‐chelating properties. In this study, we investigated deferasirox in cell and animal models to better understand its potential antifibrotic effects.</p> </sec> <sec id="jgh12720-sec-0002" sec-type="section"> <title>Methods</title> <p>The LX‐2 stellate cell line was treated with 5 μM or 50 μM deferasirox (Exjade, Novartis Pharmaceuticals Australia, North Ryde, NSW, Australia) for up to 120 h. Three‐week‐old multidrug resistance 2 null (<italic>Mdr2<sup>–/–</sup></italic>) mice received oral deferasirox or vehicle for 4 weeks (30 mg/kg/day). Cells and liver tissue were collected for assessment of fibrosis and fibrogenic gene expression.</p> </sec> <sec id="jgh12720-sec-0003" sec-type="section"> <title>Results</title> <p>In LX‐2 cells treated with 50 μM deferasirox for 12 h, α1(I)procollagen expression was decreased by 25%, with maximal reductions (10‐fold) seen following 24–120 h of treatment. Similarly, α‐smooth muscle actin (<italic>αSMA</italic>) expression was significantly lower. Alterations in matrix remodeling genes, specifically decreased expression of matrix metalloproteinase‐2 and tissue inhibitor of metalloproteinase‐2, were observed. There was no significant difference in hepatic hydroxyproline content in <italic>Mdr2<sup>–/–</sup></italic> mice following deferasirox administration (vehicle: 395 ± 27 μg/g <italic>vs</italic> deferasirox: 421 ± 33 μg/g). Similarly, no changes in the expression of fibrogenic genes were observed.</p> </sec> <sec id="jgh12720-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Despite reductions in α1(I)procollagen and αSMA expression and alterations in matrix degradation genes in LX‐2 cells, deferasirox did not exhibit antifibrotic activity in <italic>Mdr2<sup>–/–</sup></italic> mice. Given the positive outcomes seen in human trials, it may be appropriate to study deferasirox in other animal models of fibrosis and/or for a longer duration of therapy.</p> </sec> </abstract>