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Structural insight of glitazone for hepato-toxicity: Resolving mystery by PASS
Harun Patel1, Yogesh Sonawane2, Rakesh Jagtap2
1Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
Abstract:
Troglitazone causes severe hepatic injury in certain individuals and multiple mechanisms related to hepato-toxicity has been reported creating confusion. In the present study, the mechanism for the hepatic injury of glitazones was investigated by PASS. The results suggest that chromane containing glitazones are apoptic agonist (activating p53 by intrinsic pathway leading to the apoptosis) and those which do not contain the chromane are devoid of this. In case of hepato-toxicity by non-chromane glitazone and their metabolite such as M-3, RM-3, rosiglitazone and pioglitazone; PASS suggest that these chemicals are not apoptic agonist but they are the substrate for CYP enzyme (Phase-I Oxidative Enzyme) and Phase-II conjugating enzymes; interfering with bile acid metabolism rendering bile acid more toxic (cholestasis). This unmetabolised bile salt further initiates the process apoptosis via intrinsic and extrinsic pathway leading to the apoptosis. Immunoblot analysis further confirm our hypothesis that troglitazone (chromane containing glitazone), but not rosiglitazone and pioglitazone (non-chromane containing glitazone) increased the levels of p53 in a time-dependent manner. Hence our prediction related to the mechanism of hepato-toxicity by apoptosis and structural insight of glitazone can be helpful in improving the drug profile of this category.
Insights
Glitazone drugs cause liver injury through different mechanisms. Chromane-containing glitazones induce apoptosis directly, while others cause cholestasis by interfering with bile acid metabolism, leading to apoptosis.
Area of Science:
- Pharmacology
- Hepatology
- Toxicology
Background:
- Troglitazone is known to cause severe hepatic injury, with multiple proposed mechanisms leading to confusion.
- Glitazone drug class exhibits varied hepatotoxicity profiles, necessitating a clear understanding of underlying mechanisms.
Purpose of the Study:
- To investigate the distinct mechanisms of glitazone-induced hepatotoxicity using the Prediction of Activity Spectra for Substances (PASS) tool.
- To differentiate the hepatotoxic pathways based on the chemical structure of glitazone derivatives.
Main Methods:
- Utilized the PASS computational tool to predict the biological activity and toxicological mechanisms of glitazones.
- Employed immunoblot analysis to confirm the role of p53 in apoptosis induced by specific glitazone compounds.
Main Results:
- Chromane-containing glitazones were identified as apoptosis agonists, activating p53 via the intrinsic pathway.
- Non-chromane glitazones (e.g., rosiglitazone, pioglitazone) and their metabolites are substrates for CYP and Phase-II enzymes, interfering with bile acid metabolism and causing cholestasis.
- Accumulated toxic bile acids trigger apoptosis through both intrinsic and extrinsic pathways; immunoblotting confirmed increased p53 levels with troglitazone but not with rosiglitazone or pioglitazone.
Conclusions:
- Hepatotoxicity mechanisms of glitazones are structure-dependent: chromane derivatives induce apoptosis directly, while non-chromane derivatives cause cholestasis-mediated apoptosis.
- Structural insights into glitazone hepatotoxicity can guide the development of safer drug profiles within this class.