Scientific Publications by FDA Staff

Chem Res Toxicol 2016 May 16;29(5):914-23

Computed biological relations among five select treatment-related organ/tissue toxicities.

Sakellaropoulos T, Herod TJ, Alexopoulos LG, Bai JP

Drug toxicity presents a major challenge in drug development and patient care. We set to build upon previous works regarding select drug-induced toxicities to find common patterns in the mode of action of the drugs associated with these toxicities. In particular, we focused on five disparate organ toxicities, peripheral neuropathy (PN), rhabdomyolysis (RM), Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), lung injury (LI), and heart contraction-related cardiotoxicity (CT), and identified biological commonalities between and among the toxicities in terms of pharmacological targets and nearest neighbors (indirect effects) using the hyper-geometric test and a distance metric of Spearman correlation. There were 20 significant protein targets associated with two toxicities and 0 protein targets associated with three or more toxicities. Per Spearman distance, PN was closest to SJS/TEN compared to other pairs, whereas the pairs involving RM were more different than others excluding RM. The significant targets associated with RM outnumbered those associated with every one of the other four toxicities. Enrichment analysis of drug targets that are expressed in corresponding organ/tissues determined proteins that should be avoided in drug discovery. The identified biological patterns emerging from the mode of action of these drugs are statistically associated with these serious toxicities and could potentially be used as predictors for new drug candidates. The predictive power and usefulness of these biological patterns will increase with the database of these five toxicities. Furthermore, extension of our approach to all severe adverse reactions will produce useful biological commonalities for reference in drug discovery and development.