Expression of type I collagen in response to Isoniazid exposure is indirect and is facilitated by collateral induction of cytochrome P450 2E1: An in-vitro study

Abstract

We wanted to investigate whether Isoniazid (INH) can directly stimulate activation of hepatic stellate cells (HSCs) and enhance production of collagen. Treatment of human hepatic stellate cell line LX2 with or without 5μM INH for 24 to 72 hours was performed to look into content of cytochrome P450 2E1 (CYP2E1), activity of NADPH oxidase (NOX) and intracellular oxidative stress. Protein level as well as mRNA expression of alpha smooth muscle actin (α-SMA) and collagen1A1 (COL1A1) were assessed by western blot and real time PCR. In some experiments pyrazole (PY) was pre-treated to LX2 cells to induce CYP2E1 prior to INH treatment. CYP2E1 level as well as NOX activity was gradually increased with INH treatment in LX2 cells till 72 hours. Following 72 hours of INH exposure, intracellular glutathione (GSH) level was found to be reduced compared to control (p<0.01) and showed expression of α-SMA, indicating activation of HSC. We could not found any change in collagen expression in this experimental study. Pyrazole (PY) pre-treatment to LX2 cells caused significant increase in cellular CYP2E1 content associated with increase of NOX, intracellular reactive oxygen species (ROS), and expression of α-SMA and collagen1 after INH exposure. CYP2E1 is present in insignificant amount in HSCs and INH treatment could not induce collagen expression, although altered cellular oxidant levels was observed. But in LX2 cells when CYP2E1 was over-expressed by PY, INH administration provokes oxidative stress mediated stellate cells activation along with collagen type I expression.

Diallyl sulfide protects against dilated cardiomyopathy via inhibition of oxidative stress and apoptosis in mice

“…CYP2E1 is an inducible gene that is upregulated under multiple conditions, such as fasting and nutrition intake, as well as in a wide variety of pathophysiological states (2,(12)(13)(14)(15)(16)(17). In addition to metabolizing endogenous substrates and xenobiotics, CYP2E1 is the main source of cellular ROS, and its NADPH oxidase activity is higher than that of other CYP family members (9)(10)(11).…”

“…Thus, it can catalyze the reaction of NADPH and O 2 to generate reactive oxygen species (ROS) (7,8). CYP2E1 is the major enzyme for the production of cellular and mitochondrial ROS and reactive nitrogen species (RNS), which induce tissue damage mainly by damaging cellular and mitochondrial macromolecules, including mitochondrial DNA (9)(10)(11).…”

Prophylactic Antitubercular Therapy Is Associated With Accelerated Disease Progression in Patients With Crohn's Disease Receiving Anti-TNF Therapy: A Retrospective Multicenter Study

“…In addition, the finding was consistent with a previous study from India showing that a diagnostic ATT to distinguish CD from intestinal TB was associated with a higher risk of disease progression ( 8 ). It is assumed that ATT predisposing disease progression may be ascribed to the activation and proliferation of intestinal stromal cells (e.g., fibroblasts, myofibroblasts, and smooth muscle cells) or immune cells, followed by the overproduction of extracellular matrix and profibrogenic cytokines (e.g., transforming growth factor-β, interleukin-17A, and interleukin-6) ( 9 , 10 ). However, the exact mechanism of antitubercular agent-induced intestinal fibrosis needs to be elucidated in the future.…”

“…A recent study has raised a concern over patients with CD who had a history of empirical ATT before CD diagnosis because they were more apt to develop intestinal stricture ( 8 ). Indeed, several studies have demonstrated that ATT agents, including INH and RFP, have the potential to facilitate fibrosis ( 9 , 10 ). Noteworthily, once intestinal fibrosis and its associated complications such as stricture or penetration occur, there are no specific antifibrotic drugs that can reverse the disease progression yet.…”

Breaking barriers: The potential of nanosystems in antituberculosis therapy

“…INH administered via oral, intramuscular, and intravenous formulations inhibit cytochrome oxidase P450 enzymes and monoamine oxidase [ 141 ]. A critical interaction during TB treatment is its combination with RIF, which can lead to hepatotoxicity [ 142 ].…”