Investigation into the effects of Rosiglitazone on apoptosis, cell viability and cytochrome p450 expression in THP1 cultured monocytic cells
University of Wales Institute Cardiff
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Rosiglitazone is a thiazolidione (TZD) drug used to treat type 2 diabetes mellitus (T2DM). It acts via Peroxisome Proliferator Activated Receptor-gamma (PPARG) to reduce the risk of macro-vascular disease through mechanisms involving improved glucose control and decreasing the incidence of atherothrombotic events via their effects on cardiovascular risk factors. However, recent evidence showed that Rosiglitazone use caused an increased risk of myocardial infarction and dramatically increased triglyceride levels, along with other clinical complications relative to comparator drugs. This project aims to explore the apoptotic effects of this TZD drug at pharmacological (1µM) and supra-pharmacological (10µM) concentrations on THP1 monocytes over 14days. Cells treated with dimethyl sulfoxide (DMSO) were used as a vehicle control and exhibited no statistically significant effect on apoptosis (p>0.05). Cells treated with Thapsigargin were used as a positive control and exhibited a statistically significant effect on apoptosis, which killed the majority of the cell line in 3days (p<0.001). A two-way ANOVA showed that compared to control, 1µM Rosiglitazone demonstrated a non-significant effect on apoptosis (p>0.05). However the 10µM concentration did show a statistically significant effect (p<0.001) compared to the pharmacological dose. Although this concentration isn’t used clinically, over time this concentration could be reached in parts of the cell such as the endoplasmic reticulum (ER) membrane due to bioaccumulation, and cause damage due to its toxicity. A western blot analysis was carried out to compare the levels of Cytochrome P450 (CYP450) (a degradative enzyme, which metabolizes TZD drugs). Cells treated with Rosiglitazone expressed more CYP450 than those treated with Pioglitazone which was seen to have a vast decrease (>50%) in this enzyme which may lead to TZD bioaccumulation and contribute to the adverse effects that have been associated with this type of treatment. This suggests that replacing Rosiglitazone with Pioglitazone may not be beneficial to the health of diabetic patients. However, this study was carried out in vivo and therefore may not reflect the effects of these drugs in clinical trials to an accurate degree.
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