Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor

Biochem Pharmacol. 2009 Feb 15;77(4):689-99. doi: 10.1016/j.bcp.2008.05.020. Epub 2008 Jul 5.


Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors suggests that these proteins evolved to an integrated biotransformation system. Two major groups of ligand-activated nuclear receptors/xenosensors evolved: the Ah receptor (activated by aryl hydrocarbons and drugs such as omeprazole) and type 2 steroid receptors such as PXR and CAR, activated by drugs such as rifampicin, carbamazepin and phenytoin. It is increasingly recognized that there is considerable cross-talk between these xenosensors. Therefore, an attempt was made to discuss biotransformation by the Ah receptor together with that of PXR and CAR. Due to considerable species differences the emphasis is on human biotransformation. Agonists coordinately induce biotransformation due to common xenosensor-binding response elements in the regulatory region of target genes. However, whereas different groups of xenobiotics appear to more selectively stimulate CYPs (Phase I), their regulatory control largely converged in modulating Phase II metabolism and transport. Biotransformation appears to be tightly controlled to achieve efficient homeostasis of endobiotics and detoxification of dietary phytochemicals, but nuclear receptor agonists may also lead to potentially harmful drug interactions.

Publication types

  • Review

MeSH terms

  • Carrier Proteins / metabolism*
  • Constitutive Androstane Receptor
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P-450 Enzyme System / physiology*
  • Drug Interactions
  • Humans
  • Metabolic Detoxication, Phase I
  • Metabolic Detoxication, Phase II
  • Pharmaceutical Preparations / metabolism
  • Pregnane X Receptor
  • Receptor Cross-Talk / physiology*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Receptors, Aryl Hydrocarbon / physiology*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / metabolism
  • Receptors, Steroid / physiology*
  • Substrate Specificity
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Xenobiotics / pharmacokinetics
  • Xenobiotics / toxicity


  • Carrier Proteins
  • Constitutive Androstane Receptor
  • Pharmaceutical Preparations
  • Pregnane X Receptor
  • Receptors, Aryl Hydrocarbon
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • Xenobiotics
  • Cytochrome P-450 Enzyme System