Leveraging genetic interactions for adverse drug-drug interaction prediction
Fig 3
Genetic interaction provides possible mechanistic insights into DDIs.
(a) Mesalazine inhibits IKBKB, a positive regulator of NF-κB activity, and NF-κB is a transcription factor which induces NOS2 transcription. Dexamethasone can inhibit the transcription of NOS2 and facilitate degradation of NOS2. The combined use of dexamethasone and mesalazine could potentially reduce the amount of NOS2 in cells to a large extent, which may affect neurotransmission, antimicrobial and antitumoral activities. (b) Mexiletine targets NAv1.5, a sodium channel encoded by SCN5A, while arsenic trioxide targets AKT1. The transcription of SCN5A is repressed by the transcriptional repressor FOXO1. AKT1 can activate the transcription of SCN5A by phosphorylating FOXO1. The combined use of mexiletine and arsenic trioxide could inactivate the transcription of SCN5A and at the same time block the existing sodium channel, which may largely reduce sodium influx in cardiac cells.