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

Ayan Biswas,Suman Santra,Abhijit Chowdhury,Debasree Bishnu,Amal Santra,Gopal Krishna Dhali

doi:10.1155/2020/6987295

Abstract

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.

Highlights

Conclusive evidence demonstrating a cause-effect relationship between drug hepatotoxicity and development of liver fibrosis is lacking
Liver injury due to prolonged INH and RMP cotreatment in mice was assessed by measuring serum ALT level as well as histological evaluation of liver specimens
We observed a trend towards increase in serum ALT level at 4, 12, and 24 weeks of INH and RMP cotreatment (52:80 ± 3:91 IU/L at 4 weeks of treatment compared to 26:40 ± 5:41 IU/L in control mice, p < 0:01; 63:75 ± 4:45 IU/L at 12 weeks of treatment vs. 26:60 ± 2:26 IU/L in control mice, p < 0:001; and 55:50 ± 5:50 IU/L at 24 weeks of INH and RMP cotreatment against control 24:66 ± 1:52 IU/L, p < 0:001)

Summary

Introduction

Conclusive evidence demonstrating a cause-effect relationship between drug hepatotoxicity and development of liver fibrosis is lacking. In order to bring clarity on the issue, well-designed experimental studies are needed In this context, looking for evidence of activation of hepatic stellate cells (HSCs) as the key player in CH and morphological proof for production of liver fibrosis by the drug is important. 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. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis

Methods

Results

Conclusion