Simultaneous substitution of phenylalanine-305 and aspartate-318 of rat pregnane X receptor with the corresponding human residues abolishes the ability to transactivate the CYP3A23 promoter

The Journal of Pharmacology and Experimental Therapeutics
Xiulong SongBingfang Yan

Abstract

The pregnane X receptor (PXR) is a key regulator on the expression of genes involved in the elimination of chemicals. As one of the most divergent members in the nuclear receptor family, PXR is activated in a highly species-dependent manner by certain chemicals. Pregnenolone 16alpha-carbonitrile (PCN), a glucocorticoid antagonist, efficaciously activates rodent but not human PXR. This study was undertaken to investigate the structural basis for PCN-mediated activation of rat PXR. A series of rat-human chimeric PXRs were prepared to gradually replace the ligand-binding domain of human PXR with the corresponding rat sequence at an increasing length of 20 residues. Cotransfection experiments established that region(306-326) acted as a transitional conjunction from none to full PCN responsive status. Site-directed mutagenesis study identified two residues (Phe-305 and Asp-318) that were critical in supporting PCN-mediated activation, and simultaneous substitution of both residues abolished the ability of rat PXR to transactivate the CYP3A23 promoter. In addition, substitutions on Phe-305, Asp-318, or both markedly reduced the basal transcriptional activity, and the reduction occurred with the CYP3A4 but not CYP3A23 promoter. Furthe...Continue Reading

References

Oct 24, 1998·Genes & Development·B BlumbergR M Evans
Jul 23, 1999·Archives of Biochemistry and Biophysics·H ZhangB Yan
Oct 18, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·R Krishna, L D Mayer
Mar 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·J L StaudingerS A Kliewer
Mar 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·W XieR M Evans
Jul 24, 2001·Current Drug Metabolism·M ShouT H Rushmore
Nov 8, 2001·Journal of Clinical Pharmacology·K VenkatakrishnanD J Greenblatt
Jan 25, 2002·Annual Review of Pharmacology and Toxicology·Bryan GoodwinSteven A Kliewer
Mar 27, 2002·The Pharmacogenomics Journal·U Brinkmann, M Eichelbaum
Oct 9, 2002·Current Drug Metabolism·Thomas H Rushmore, A-N Tony Kong
Mar 8, 2003·The Journal of Biological Chemistry·Yuxin LiBingfang Yan
Jul 29, 2003·Clinical Pharmacokinetics·Mikko NiemiKari T Kivistö
Aug 12, 2003·Journal of Molecular Biology·Ryan E WatkinsMatthew R Redinbo
Jan 15, 2004·Molecular Pharmacology·Rommel G TironaRichard B Kim
Apr 20, 2004·Advances in Experimental Medicine and Biology·Valerie Billard
Apr 22, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hannah M JonesJ Brian Houston
Jul 30, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuzhong MaBingfang Yan

❮ Previous
Next ❯

Citations

May 8, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Juan P HernandezWilliam S Baldwin
Aug 1, 2006·Drug Metabolism Reviews·Lesley A StanleyC Roland Wolf
Mar 16, 2017·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Chun Ling Seow, Aik Jiang Lau
Oct 25, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aik Jiang LauThomas K H Chang
Sep 28, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jian Yang, Bingfang Yan

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.