4.7:
Transducer Mechanism: Nuclear Receptors
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Nuclear receptors, or NRs, are transcription factors that bind ligands, such as hormones, lipids, and vitamins, to alter gene expression. Currently, they are targeted by nearly 15% of approved drugs. NRs can be of two main classes: Class I NRs are cytosolic. They bind steroid hormones and undergo dimerization. The homodimers translocate to the nucleus and interact with DNA response elements, recruiting co-activators or co-repressors. Co-activators recruit enzymes to unzip the DNA helix to initiate transcription. In contrast, co-repressors use enzymes to keep the DNA tightly packed, blocking transcription. For example, tamoxifen selectively blocks estrogen receptors or ERs and helps treat ER-positive breast tumors. Class II NRs exist in the nucleus as DNA-bound heterodimers with retinoid X receptors and remain bound to co-repressors When a lipid ligand binds these NRs, the co-repressors detach, and a co-activator is recruited. Fenofibrate, a lipid-lowering drug, binds class II NRs like PPAR to activate genes that regulate fatty acid metabolism and decrease plasma triglyceride levels.
4.7:
Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
- Class I nuclear receptors consist of endocrine receptors such as estrogen, androgen, and glucocorticoid receptors. These cytosolic receptors remain monomeric, attached to a heat shock protein until bound by a ligand. Ligand binding allows the heat shock protein to dissociate and induce receptor homodimerization. As the homodimer moves to the nucleus, it binds DNA response elements and either initiates or suppresses gene transcription. Recent pharmacological advances have led to the development of selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene. SERMs show tissue-specific action on the estrogen receptors and help treat osteoporosis and breast cancer. Tamoxifen is an antagonist that binds breast estrogen receptors and blocks them, preventing cancer cell multiplication. In contrast, the same drug acts as an agonist upon binding the estrogen receptors in bones. It helps activate them and preserve bones while increasing bone density.
- Class II nuclear receptors consist of the peroxisome proliferator-activated receptor (PPAR), the liver oxysterol receptor (LXR), the farnesoid receptor (FXR), and the xenobiotic receptor. They control the transcription of genes involved in lipid metabolism, glucose homeostasis, and inflammatory response. They exist as heterodimers with retinoid X receptors and are located on DNA. Without a ligand, they remain attached to co-repressors and prevent gene transcription. The co-repressor detaches as the ligand binds these heterodimers, allowing the co-activator to attach and unzip the DNA for transcription. Class II nuclear receptors are targeted by lipid-lowering drugs such as clofibrate and fenofibrate, antidiabetics such as thiazolidinediones, and various non-steroidal drugs. Apart from this, xenobiotic receptors regulate the expression of the drug-metabolizing enzyme CYP3A, which is responsible for the pharmacokinetics of 60% of prescription drugs.
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Transducer MechanismNuclear ReceptorsNRsTranscription FactorsGene TranscriptionCellular PathwaysReproductionDevelopmentMetabolismSmall Lipophilic LigandsDrug TargetsSoluble Family MembersClass I Nuclear ReceptorsEndocrine ReceptorsEstrogen ReceptorsAndrogen ReceptorsGlucocorticoid ReceptorsCytosolic ReceptorsHeat Shock ProteinLigand BindingReceptor HomodimerizationDNA Response ElementsGene Transcription Initiation/suppressionSelective Estrogen Receptor Modulators (SERMs)TamoxifenRaloxifeneOsteoporosis TreatmentBreast Cancer Treatment