Open AccessIdentification of a human nuclear receptor defines a new signaling pathway for CYP 3 A induction
Author(s) -
Göran Bertilsson,
Jessica Heidrich,
Kristian Svensson,
Michael Åsman,
Lena Jendeberg,
Mona Sydow-Bäckman,
Rolf Ohlsson,
Hans Postlind,
Patrik Blomquist,
Anders Berkenstam
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.21.12208
Subject(s) - pregnane x receptor , nuclear receptor , biology , gene , cyp3a , receptor , activator (genetics) , constitutive androstane receptor , computational biology , signal transduction , microbiology and biotechnology , cytochrome p450 , genetics , biochemistry , enzyme , transcription factor
Nuclear receptors regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes. Here, a computational search approach based on iteratively built hidden Markov models of nuclear receptors was used to identify a human nuclear receptor, termed hPAR, that is expressed in liver and intestines. hPAR was found to be efficiently activated by pregnanes and by clinically used drugs including rifampicin, an antibiotic known to selectively induce human but not murineCYP3A expression. TheCYP3A drug-metabolizing enzymes are expressed in gut and liver in response to environmental chemicals and clinically used drugs. Interestingly, hPAR is not activated by pregnenolone 16α-carbonitrile, which is a potent inducer of murineCYP3A genes and an activator of the mouse receptor PXR.1. Furthermore, hPAR was found to bind to and trans-activate through a conserved regulatory sequence present in human but not murineCYP3A genes. These results provide evidence that hPAR and PXR.1 may represent orthologous genes from different species that have evolved to regulate overlapping target genes in response to pharmacologically distinctCYP3A activators, and have potential implications for thein vitro identification of drug interactions important to humans.