The In Vitro Pharmacological Profile of Drugs as a Proxy Indicator of Potential In Vivo Organ Toxicities

Chem Res Toxicol. 2016 Apr 18;29(4):637-48. doi: 10.1021/acs.chemrestox.5b00470. Epub 2016 Mar 16.


The potential of a drug to cause certain organ toxicities is somehow implicitly contained in its full pharmacological profile, provided the drug reaches and accumulates at the various organs where the different interacting proteins in its profile, both targets and off-targets, are expressed. Under this assumption, a computational approach was implemented to obtain a projected anatomical profile of a drug from its in vitro pharmacological profile linked to protein expression data across 47 organs. It was observed that the anatomical profiles obtained when using only the known primary targets of the drugs reflected roughly the intended organ targets. However, when both known and predicted secondary pharmacology was considered, the projected anatomical profiles of the drugs were able to clearly highlight potential organ off-targets. Accordingly, when applied to sets of drugs known to cause cardiotoxicity and hepatotoxicity, the approach is able to identify heart and liver, respectively, as the organs where the proteins in the pharmacological profile of the corresponding drugs are specifically expressed. When applied to a set of drugs linked to a risk of Torsades de Pointes, heart is again the organ clearly standing out from the rest and a potential protein profile hazard is proposed. The approach can be used as a proxy indicator of potential in vivo organ toxicities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiotoxicity / etiology*
  • Cardiotoxicity / genetics
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / genetics
  • Computational Biology / methods
  • Heart / drug effects
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Myocardium / metabolism
  • Risk
  • Torsades de Pointes / chemically induced*
  • Torsades de Pointes / genetics
  • Toxicological Phenomena*
  • Transcriptome