title: Structural insight of glitazone for hepato-toxicity: Resolving mystery by PASS.
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.
authors: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors: Harun
authors: H
authors: Patel
authors: Division of Computer Aided Drug Design and Discovery, Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule) 425405, Maharashtra, India.
authors: Yogesh
authors: Y
authors: Sonawane
authors: Division of Computer Aided Drug Design and Discovery, Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule) 425405, Maharashtra, India.
authors: Rakesh
authors: R
authors: Jagtap
authors: Division of Computer Aided Drug Design and Discovery, Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule) 425405, Maharashtra, India.
authors: Kiran
authors: K
authors: Dhangar
authors: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors: Neeta
authors: N
authors: Thapliyal
authors: Division of Computer Aided Drug Design and Discovery, Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule) 425405, Maharashtra, India.
authors: Sanjay
authors: S
authors: Surana
authors: Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim (Surat) 394110, Gujarat, India.
authors: Malleshappa
authors: M
authors: Noolvi
authors: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors: Mahamadhanif S
authors: MS
authors: Shaikh
authors: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors: Rajesh A
authors: RA
authors: Rane
authors: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa. Electronic address: karpoormath@ukzn.ac.za.
authors: Rajshekhar
authors: R
authors: Karpoormath
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*
chemical_list: D045162:Thiazolidinediones
keywords: Apoptosis; Docking; Glitazone; Immunoblot analysis; PASS; Troglitazone