CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

Pharmacogenomics J. 2004;4(2):91-101. doi: 10.1038/sj.tpj.6500222.

Abstract

This study reports that Cyp3a41 gene contains 13 exons and is localized on the chromosome 5. CYP3A41 is a female-specific isoform that is predominantly expressed in the liver. Estrogen signaling is not responsible for its female specificity. CYP3A41 expression in kidney and brain is observed only in 50% of mice examined. PXR mediates dexamethasone-dependent suppression of CYP3A41. In contrast to CYP3A11, CYP3A41 expression is not induced by pregnenolone-16alpha-carbonitrile (PCN) in wild-type mice, but is significantly suppressed by PCN in PXR(-/-) mice. Phenobarbital and TCPOBOP induce CYP3A11 expression only in the presence of CAR, but have no effect on CYP3A41 expression. Immunoblot and erythromycin demethylase activity analysis reveal robust CYP3A induction after PCN treatment, which is poorly correlated to CYP3A41. These findings suggest a differential role for CAR/PXR in regulating individual CYP3A isoforms by previously characterized CYP3A inducers.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics*
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / physiology
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Oxidoreductases / biosynthesis
  • Oxidoreductases / genetics*
  • Oxidoreductases, N-Demethylating / biosynthesis
  • Oxidoreductases, N-Demethylating / genetics*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / biosynthesis
  • Receptors, Steroid / deficiency
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*

Substances

  • Isoenzymes
  • Membrane Proteins
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • constitutive androstane receptor
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Cyp3a41a protein, mouse
  • Oxidoreductases
  • Aryl Hydrocarbon Hydroxylases
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating