More than 75% of the elderly population takes multiple drugs in the United States and adverse drug reactions are one of the leading causes of drug-related deaths. Among these reactions, drug-drug interactions (DDI) arise when one drug alters the metabolism of the other. Moreover the two drugs can synergistically affect molecular events that result in toxicities. The presented study aims to understand the role of transcription factors in DDIs. Reporter plasmids were constructed possessing the response elements of common transcriptional regulators of cythochrome P450 enzymes, including CYP3A4. Cell lines, e.g. Huh-7, as well as primary hepatocytes were transfected with reporter plasmids bearing the response elements of various transcriptional factors such as pregnane X receptor, reporting on the transcriptional activation of enzymatic activity upon exposure to different drugs. The changes in the transcription of these receptors were monitored via the expression levels of a green fluorescent protein. In addition, a second fluorescent protein was employed as an internal reference for normalization. This protein was included in the same construct, resulting in a dual-promoter reporter plasmid transfected into mammalian cells. This way, different signatures of the regulatory proteins were collected upon exposure to various conditions. The latest results on the role played by transcriptional factors in the regulation of DDIs will be presented.<br/>

Elucidation of drug-drug interactions at the transcriptional level in hepatocytes

255th National Meeting (2018)

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