Novel orphan nuclear receptor-coregulator interactions controlling anti-cancer drug metabolism

Radharani Gollamudi, Divya Gupta, Sanjay Goel, Sridhar Mani

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

In recent years, it has become clear that drug metabolizing enzymes and efflux transporters are directly under the control of tissue-specific orphan receptors, mainly pregnenolone x-receptor (PXR), and constitutive androstene receptor (CAR), that coordinately regulate their transcription. The consequences of xenobiotic activation of these receptors leads to unpredictability of drug kinetics and in some cases drug pharmacodynamics. Since receptor specific co-regulators are critically involved in this process, this review serves to highlight important new advances in this area of research. Specifically, this review focuses on co-regulator interactions described for PXR and CAR and some models that provide an explanation for receptor activation and repression. PXR is basally repressed and is activated in a ligand and tissue specific manner through a complex shift in co-repressor (Silencing mediator of retinoid and thyroid receptor (SMRT) and nuclear receptor co-repressor (N-CoR)) and co-activator (Steroid receptor coactivator-1(SRC-1), PPAR and glucocorticoid receptor coactivator-1(PGC-1), Hepatocyte nuclear factor 4 (HNF-4)) interactions favoring activation. Other higher order complexes impinge on this shift and include small heterodimer partner (SHP) mediated inhibition of co-activators and still others involved in histone acetylation/ deacetylation (e.g., SWI/SNF, HDACs). Similar interactions have been proposed for CAR and these will be discussed in detail. Finally, this review will focus on the implications of understanding receptor-co-regulator interactions with the eventual aim of assessing polymorphisms in this transcriptional complex as a method to normalize the effects of drug metabolism.

Original languageEnglish (US)
Pages (from-to)611-613
Number of pages3
JournalCurrent Drug Metabolism
Volume9
Issue number7
DOIs
StatePublished - 2008

Fingerprint

Androstenes
Orphan Nuclear Receptors
Metabolism
Co-Repressor Proteins
Pregnenolone
Chemical activation
Hepatocyte Nuclear Factor 4
Nuclear Receptor Coactivator 1
Pharmaceutical Preparations
Neoplasms
Peroxisome Proliferator-Activated Receptors
Glucocorticoid Receptors
Retinoids
Pharmacodynamics
Xenobiotics
Tissue
Acetylation
Histones
Thyroid Gland
Transcription

Keywords

  • Cancer chemotherapy
  • Coregulators
  • Histone acetylation
  • Nuclear receptors
  • Pregnenolone X receptor

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this

Novel orphan nuclear receptor-coregulator interactions controlling anti-cancer drug metabolism. / Gollamudi, Radharani; Gupta, Divya; Goel, Sanjay; Mani, Sridhar.

In: Current Drug Metabolism, Vol. 9, No. 7, 2008, p. 611-613.

Research output: Contribution to journalArticle

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