Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism

Background & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. W...

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Main Authors: Ayan Biswas, Suman Santra, Debasree Bishnu, Gopal Krishna Dhali, Abhijit Chowdhury, Amal Santra
Format: Article
Language:English
Published: Wiley 2020-01-01
Series:International Journal of Hepatology
Online Access:http://dx.doi.org/10.1155/2020/6987295
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author Ayan Biswas
Suman Santra
Debasree Bishnu
Gopal Krishna Dhali
Abhijit Chowdhury
Amal Santra
author_facet Ayan Biswas
Suman Santra
Debasree Bishnu
Gopal Krishna Dhali
Abhijit Chowdhury
Amal Santra
author_sort Ayan Biswas
collection DOAJ
description Background & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. We sought evidence of the production of hepatic fibrosis on long-term INH-RMP treatment through experiments in BALB/c mice exposed to INH-RMP. Methods. A combined dose of INH (50 mg) and RMP (100 mg) per kg body weight per day was administered to mice by oral gavage, 6 days a week, for 4 to 24 weeks for the assessment of liver injury, oxidative stress, and development of hepatic fibrosis, including demonstration of changes in key fibrogenesis linked pathways and mediators. Results. Progressive increase in markers of hepatic stellate cell (HSC) activation associated with changes in matrix turnover was observed between 12 and 24 weeks of INH-RMP treatment along with the elevation of liver collagen content and significant periportal fibrosis. These were associated with concurrent apoptosis of the hepatocytes, increase in hepatic cytochrome P450 2E1 (CYP2E1), NADPH oxidase (NOX) activity, and development of hepatic oxidative stress. Conclusions. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis.
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spelling doaj-art-22c49cdde72743298f54d2a5356f6b4e2025-02-03T00:58:57ZengWileyInternational Journal of Hepatology2090-34482090-34562020-01-01202010.1155/2020/69872956987295Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent MechanismAyan Biswas0Suman Santra1Debasree Bishnu2Gopal Krishna Dhali3Abhijit Chowdhury4Amal Santra5Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaCentre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaCentre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaCentre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaCentre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaCentre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, IndiaBackground & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. We sought evidence of the production of hepatic fibrosis on long-term INH-RMP treatment through experiments in BALB/c mice exposed to INH-RMP. Methods. A combined dose of INH (50 mg) and RMP (100 mg) per kg body weight per day was administered to mice by oral gavage, 6 days a week, for 4 to 24 weeks for the assessment of liver injury, oxidative stress, and development of hepatic fibrosis, including demonstration of changes in key fibrogenesis linked pathways and mediators. Results. Progressive increase in markers of hepatic stellate cell (HSC) activation associated with changes in matrix turnover was observed between 12 and 24 weeks of INH-RMP treatment along with the elevation of liver collagen content and significant periportal fibrosis. These were associated with concurrent apoptosis of the hepatocytes, increase in hepatic cytochrome P450 2E1 (CYP2E1), NADPH oxidase (NOX) activity, and development of hepatic oxidative stress. Conclusions. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis.http://dx.doi.org/10.1155/2020/6987295
spellingShingle Ayan Biswas
Suman Santra
Debasree Bishnu
Gopal Krishna Dhali
Abhijit Chowdhury
Amal Santra
Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
International Journal of Hepatology
title Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
title_full Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
title_fullStr Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
title_full_unstemmed Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
title_short Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism
title_sort isoniazid and rifampicin produce hepatic fibrosis through an oxidative stress dependent mechanism
url http://dx.doi.org/10.1155/2020/6987295
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