IDENTIFICATION OF A HUMAN NUCLEAR RECEPTOR DEFINES A NEW SIGNALING PATHWAY FOR CYP3A INDUCTION

Nuclear receptors regulate metabolic pathways in response to changes i n the environment by appropriate alterations in gene expression of key metabolic enzymes, Here, a computational search approach based on ite ratively built hidden Markov models of nuclear receptors was used to i dentify a human nuclear receptor, termed hPAR, that is expressed in li ver and intestines. hPAR was found to be efficiently activated by preg nanes and by clinically used drugs including rifampicin, an antibiotic known to selectively induce human but not murine CYP3A expression. Th e CYP3A drug-metabolizing enzymes are expressed in gut and liver in re sponse to environmental chemicals and clinically used drugs. Interesti ngly, hPAR is not activated by pregnenolone 16 alpha-carbonitrile, whi ch is a potent inducer of murine CYP3A genes and an activator of the m ouse receptor PXR.1. Furthermore, hPAR was found to bind to and trans- activate through a conserved regulatory sequence present in human but not murine CYP3A genes. These results provide evidence that hPAR and P XR.1 may represent orthologous genes from different species that have evolved to regulate overlapping target genes in response to pharmacolo gically distinct CYP3A activators, and have potential implications for the in vitro identification of drug interactions important to humans.