MICRORNA REGULATION OF THE UGT2 SUB-FAMILY OF DETOXIFYING ENZYMES

Aimee Kristina Sutliff

A great deal of work has been done to characterize the expression and activity of drug metabolizing enzymes. Developing a more useful model of drug efficacy requires knowledge of expression levels of enzymes within target tissues. Studies that have shown a low correlation between mRNA and protein levels for many genes have highlighted the gap in knowledge of what factors may interfere in the translation of mRNA to protein. microRNA are short nucleotide strands that have been studied extensively for their role in gene regulation. Under normal circumstances, microRNA binds to mRNA to fine-tune expression by inhibiting translation. Individual variation in microRNA expression may impact gene regulation in healthy tissues and could become dysregulated under pathological conditions, causing gene expression to become dysregulated as a result. Uridine 5’-disphospho-glucuronosyltransferases (UGTs) are phase II metabolizing enzymes that conjugate a polar sugar to a non-polar compound in order to facilitate elimination. UGTs are critical for the detoxification of many compounds, including carcinogenic compounds found in cigarettes, like tobacco specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs). Regulation of UGTs by microRNA may alter expression and could significantly contribute to the inter-individual variability observed in human tissue samples. The first part of this dissertation is focused on hepatic UGT2B enzymes and two different microRNA: miR-216b-5p and miR-485-5p. The in silico analysis prediction that miR-216b-5p binds to UGT2Bs 2B4, 2B7 and 2B10 is explored in human liver cancer cell lines. A follow-up study sought to measure the levels of several microRNA candidates as well as UGT2Bs in healthy human liver samples and identify any negative correlation indicative of a regulatory role for the candidate microRNA. miR-485-5p was significantly negatively correlated with UGT2B10. Further analysis revealed a regulatory relationship with UGT2B10, as predicted for miR-485-5p but also for UGT2B7, which was not predicted. The potential consequences of these interactions is thoroughly discussed. The latter part of this dissertation explores the regulation of UGT2A1 in human lung by miR-196a-5p and miR-196b-5p and how it may impact risk of cancer in smokers as a result of polycyclic aromatic hydrocarbon exposure.

MICRORNA REGULATION OF THE UGT2 SUB-FAMILY OF DETOXIFYING ENZYMES

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