title: Cytotoxicity of 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) and analogues in wild type and CYP3A4 stably transfected HepG2 cells.
abstract: The thiazolidinedione (TZD) ring is a constituent of the glitazones that are used to treat type II diabetes. Liver injury has been reported following chronic glitazone use; however, they do not produce hepatic damage in common laboratory animal species. In contrast, 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) causes hepatotoxicity in rats. DCPT toxicity is dependent upon the presence of an intact TZD ring and cytochrome P450 (CYP)-mediated biotransformation. To further investigate TZD ring-induced toxicity, DCPT and several structural analogues or potential metabolites were tested in vitro using wild type human hepatoma HepG2 and HepG2 cells stably transfected with the CYP3A4 isozyme. CYP3A4 activity was confirmed by measuring testosterone 6β-hydroxylation. Both cell lines were treated with 0-250 μM of the compounds in Hanks' balanced salt solution. Cell viability was measured after 24 h. DCPT and S-(3,5-dichlorophenyl)aminocarbonyl thioglycolic acid (DCTA) were the most toxic compounds of the series. Furthermore, DCPT was significantly more toxic in transfected cells (LC50=160.2±5.9 μM) than in wild type cells (LC50=233.0±19.7 μM). Treatment with a CYP3A4 inhibitor or inducer attenuated or potentiated DCPT cytotoxicity, respectively. These results suggest that DCPT-induced cytotoxicity in the transfected HepG2 cells is partially dependent on CYP3A4.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences, Philadelphia, PA 19104, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Frederick
authors.forename: Erina Y
authors.initials: EY
authors.lastname: Jacinto
authors.forename: Niti N
authors.initials: NN
authors.lastname: Patel
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rushmore
authors.forename: Ruy
authors.initials: R
authors.lastname: Tchao
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Harvison
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000633:toxicity; D007654:Ketoconazole / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism; D045162:Thiazolidinediones / Q000633:toxicity*; D014162:Transfection
chemical_list: C532666:3-(3,5-dichlorophenyl)-2,4-thiazolidinedione; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D003907:Dexamethasone; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; D007654:Ketoconazole