دورية أكاديمية
Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat.
| العنوان: | Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat. |
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| المؤلفون: | Martín PL; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Ceccatto P; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Razori MV; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Francés DEA; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Arriaga SMM; Area Bioquímica Clínica, Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Pisani GB; Area Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Martínez AI; Area Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Sánchez Pozzi EJ; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Roma MG; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina., Basiglio CL; Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina basiglio@ifise-conicet.gov.ar.; Area Bioquímica Clínica, Facultad de Ciencias Bioquímicas y Farmacéuticas (U.N.R.), Rosario, Argentina. |
| المصدر: | Clinical science (London, England : 1979) [Clin Sci (Lond)] 2019 Jan 11; Vol. 133 (1), pp. 117-134. Date of Electronic Publication: 2019 Jan 11 (Print Publication: 2019). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Portland Press on behalf of the Medical Research Society and the Biochemical Society Country of Publication: England NLM ID: 7905731 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1470-8736 (Electronic) Linking ISSN: 01435221 NLM ISO Abbreviation: Clin Sci (Lond) Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London : Portland Press on behalf of the Medical Research Society and the Biochemical Society Original Publication: London, Medical Research Society. |
| مواضيع طبية MeSH: | Oxidative Stress*, Antioxidants/*pharmacology , Cholestasis/*prevention & control , Heme Oxygenase (Decyclizing)/*biosynthesis , Hemin/*pharmacology , Liver/*drug effects, Animals ; Bile/metabolism ; Bilirubin/metabolism ; Catalase/metabolism ; Cholestasis/chemically induced ; Cholestasis/enzymology ; Cholestasis/pathology ; Disease Models, Animal ; Enzyme Induction ; Glutathione/metabolism ; Liver/enzymology ; Liver/pathology ; Male ; Rats, Wistar ; Superoxide Dismutase/metabolism ; tert-Butylhydroperoxide |
| مستخلص: | We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert -butylhydroperoxide ( t BuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by t BuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background. (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.) |
| فهرسة مساهمة: | Keywords: Bilirubin; acute cholestasis; heme oxygenase 1; hepatocanalicular transport; oxidative stress |
| المشرفين على المادة: | 0 (Antioxidants) 743LRP9S7N (Hemin) 955VYL842B (tert-Butylhydroperoxide) EC 1.11.1.6 (Catalase) EC 1.14.14.18 (Heme Oxygenase (Decyclizing)) EC 1.14.14.18 (Hmox1 protein, rat) EC 1.15.1.1 (Superoxide Dismutase) GAN16C9B8O (Glutathione) RFM9X3LJ49 (Bilirubin) |
| تواريخ الأحداث: | Date Created: 20181213 Date Completed: 20191022 Latest Revision: 20191022 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1042/CS20180675 |
| PMID: | 30538149 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1470-8736 |
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| DOI: | 10.1042/CS20180675 |