title: Advantages of cell-based high-volume screening assays to assess nuclear receptor activation during drug discovery.
abstract: BACKGROUND
  Adverse drug effects and drug-drug interactions (DDIs) can be elicited by the activation of several nuclear receptors (NRs). Of the NRs that regulate expression of drug metabolizing enzymes and transporters and alter cellular processes, the most important are pregnane X receptor, constitutive androstane receptor and aryl hydrocarbon receptor. Screening for the activation of these receptors can be achieved during drug discovery by using various high-throughput analyses including ligand binding and transactivation assays.
  
  
  METHODS
  This review focuses on the importance of screening for NR activation during drug discovery and includes a discussion of the various assays to evaluate activation of NRs by xenobiotics. It also describes screening for species-specific NR activation to attenuate the use of animals in toxicology studies and to identify complications associated with drug metabolism and clearance that may occur during pharmacokinetic analyses.
  
  
  CONCLUSIONS
  Given the potential for adverse drug effects and DDIs during all phases of drug elimination, NR screening should occur early in drug discovery. Such screening could be used in structure-activity relationship studies to guide chemists in altering compound structures to eliminate the NR-binding and activation properties on priority compounds. Early screening can also reduce the risk of adverse drug effects, identify novel therapeutic agents and decrease the number of animals used in drug development. Overall, performing these types of assays described here could decrease drug development costs, alleviate the liability associated with drugs that activate NR and prevent unsafe drugs from entering the marketplace.
authors.affiliation: Puracyp, Inc. , 5900 Sea Lion Place, Suite 130, Carlsbad, CA 92010 , USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Pinne
authors.forename: Judy L
authors.initials: JL
authors.lastname: Raucy
mesh_terms: D000818:Animals; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D015262:Xenobiotics / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics
keywords: aryl hydrocarbon receptor; cell-based transactivation assays; constitutive androstane receptor; cytochrome P450; drug discovery; high-throughput screening; nuclear receptor activation; pregnane X receptor