The goal of pharmacogenetics is to better understand human response to both environmental toxins and drug treatment. Recently, several laboratories have investigated the hypothesis that microRNA regulation of drug metabolizing enzymes may influence their expression and ultimately effect enzymatic activity and patient drug toxicities. Researchers at the Pennsylvania State Hershey College of Medicine and Washington State University, Spokane, identified miR-491-3p as a microRNA regulator of UDP-Glucuronosyltransferase (UGT) gene family members. In their article ‘Regulation of the UDP-Glucuronosyltransferase 1A1 Expression and Activity by MicroRNA 491-3p’, miR-491-3p is identified to target and bind with the common 3’ UTR of several UGT1A sub family gene members. Endogenous miR-491-3p expression in vitro had a significant impact on the gene expression of UGT1A1, UGT1A3, and UGT1A6 genes. miR-491-3p expression also effected UGT1A1 protein expression and metabolic activity against the substrate raloxifene, a chemotherapeutic drug used in the prevention and treatment of breast cancer.
Interestingly, Dluzen et. al. also observed inter-individual variable expression of miR-491-3p in human liver. Nearly one-third of the 39 liver samples analyzed lacked endogenous expression of miR-491-3p. Liver expression levels of miR-491-3p were significantly inversely correlated with expression of several UGT1A mRNAs, including UGT1A3 and UGT1A6. Importantly, this study identifies a novel regulator of UGT1A gene expression in the liver and represents a potential novel contributor that impacts patient drug response. Additionally, miR-491-3p expression levels in the liver may serve as a biomarker for UGT1A enzymatic expression in the liver. The authors noted that miR-491-3p is also expressed in several other metabolic tissues and may influence tissue-specific UGT enzymatic activity as well. This is the first study identifying miRNA regulators of members of the UGT enzyme family.
The article is in press and can be found here: http://www.ncbi.nlm.nih.gov/pubmed/24399855
Dluzen, D.F., Sun, D., Salzberg, A.C., Jones, N., Bushey, R.T., Roberston, G.P., Lazarus, P. Regulation of UDP-Glucuronosyltransferase 1A1 Expression and Activity by MicroRNA 491-3p. J Pharmacol Exp Ther (2014), 348(3): 465-477.