Abstract

 
 
 
 Purpose: To determine the effect of rosiglitazone on the levels of the cardiotoxic arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), in the human liver hepatocellular carcinoma cell line, HepG2.
 Methods: HepG2 cells were treated with thiazolidinedione rosiglitazone and the mRNA and protein expressions of cytochrome P450 4F2 (CYP4F2) responsible for synthesizing 20-HETE were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The levels of 20-HETE were evaluated using liquid chromatography/mass spectrometry (LC-MS).
 Results: Rosiglitazone significantly increased the levels of CYP4F2 mRNA and protein when compared with the control group (p < 0.05). This was correlated with significantly increased 20-HETE levels in the culture medium of rosiglitazone-treated cells in a dose-dependent manner (p < 0.05). The PPARγ antagonist, GW9662, significantly repressed the increased production of 20-HETE and CYP4F2 mRNA protein (p < 0.05).
 Conclusion: Rosiglitazone increases the synthesis of 20-HETE via activation of PPARγ receptor and upregulation of CYP4F2. These findings may provide an additional explanation, at least in part, for the unwanted side effects of rosiglitazone on the cardiovascular system.
 
 
 
Highlights
Thiazolidinediones are activators of peroxisome proliferator-activated receptor gamma (PPARγ)
Quantitative RT-PCR analysis of the cytochrome P450 4F2 (CYP4F2) gene showed a concentration-dependent increase in the expression of CYP4F2 in HepG2 cells treated with rosiglitazone (Figure 1)
When the cells were pretreated with GW9662, CYP4F2 mRNA expression was significantly (p < 0.05) lower than in HepG2 cells treated with 10 μM rosiglitazone only
Summary
Thiazolidinediones are activators of peroxisome proliferator-activated receptor gamma (PPARγ). Rosiglitazone was evaluated for cardiac outcomes in a clinical trial study and it found out that hospitalization, due to cardiovascular event, was more significant in diabetic patients receiving rosiglitazone, in combination with other anti-diabetic drugs [4]. It was in a study of the United Kingdom Prospective. The current study investigated the effect of rosiglitazone on the expression of 20HETE-synthesizing CYP4 genes and the production of 20-HETE in HepG2 cells. To determine the role of PPARγ receptors in CYP4 expression and 20HETE production, the PPARγ antagonist GW9662 (10 μM) was added 3 h before thiazolidinedione treatment. All statistical analyses were performed using SAS (ver. 9.1.3; SAS Institute, Cary, NC, USA)
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