Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor

Toxicol Appl Pharmacol. 2003 Nov 15;193(1):66-72. doi: 10.1016/j.taap.2003.08.001.

Abstract

Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2). These genes control the metabolism (CYP3A subfamily) and aspects of the pharmacokinetics (MDR1 and OATP2) of both endogenous and xenobiotic compounds. Since PXR is important in understanding the actions of endocrine disruptors (EDs), we determined the ability of suspected EDs to interact with PXR. In our study, 7 of 54 xenobiotics compounds interacted with PXR, including methoxychlor and benzophenone. All of the chemicals activated PXR in vitro and induced CYP3A mRNA in the male rat liver. In addition, CYP2C11 was also induced by some PXR agonists and converted methoxychlor into xenoestrogen. These findings suggest that some EDs affect sex hormone receptor indirectly by induction of metabolic enzyme via PXR, to produce rapidly higher concentrations of effective metabolites, leading to disturbance of the endocrine system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Benzophenones / metabolism*
  • Benzophenones / toxicity
  • Cytochrome P-450 CYP3A
  • Enzyme Induction / drug effects
  • Estrogen Receptor alpha
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Male
  • Methoxychlor / metabolism*
  • Methoxychlor / toxicity
  • Microsomes, Liver / enzymology
  • Oxidoreductases, N-Demethylating / biosynthesis*
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Pregnane X Receptor
  • RNA / chemistry
  • RNA / genetics
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / metabolism
  • Receptors, Steroid / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects
  • Two-Hybrid System Techniques
  • Xenobiotics / metabolism*
  • Xenobiotics / toxicity

Substances

  • Benzophenones
  • Estrogen Receptor alpha
  • Pregnane X Receptor
  • Receptors, Androgen
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Steroid
  • Xenobiotics
  • RNA
  • benzophenone
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Methoxychlor