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Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2020
Tetsuya Fujimura, Kenichi Takayama, Satoru Takahashi, Satoshi Inoue
The steroid and xenobiotic receptor (SXR), also known as the human pregnane X receptor, constitutes members of the nuclear receptor superfamily of ligand-activated transcription factors [44, 45]. The elimination of dihydrotestosterone (DHT), which is the active androgen in the prostate, is critical for successful endocrine therapy for PC. Testosterone is inactivated in the liver and prostate by Cytochrome P450 (CYP) enzymes [46–48]. SXR regulates CYP3A4 and CYP2B6, which are responsible for the hydroxylation of testosterone in the liver and prostate [48–50]. SXR and its target genes CYP3A4 and CYP2B6 participate in the regulation of PC via intra-prostatic testosterone metabolism [49–52].
Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2019
Tetsuya Fujimura, Kenichi Takayama, Satoru Takahashi, Satoshi Inoue
The steroid and xenobiotic receptor (SXR), also known as the human pregnane X receptor, constitutes members of the nuclear receptor superfamily of ligand-activated transcription factors [44, 45]. The elimination of dihydrotestosterone (DHT), which is the active androgen in the prostate, is critical for successful endocrine therapy for PC. Testosterone is inactivated in the liver and prostate by Cytochrome P450 (CYP) enzymes [46–48]. SXR regulates CYP3A4 and CYP2B6, which are responsible for the hydroxylation of testosterone in the liver and prostate [48–50]. SXR and its target genes CYP3A4 and CYP2B6 participate in the regulation of PC via intra-prostatic testosterone metabolism [49–52].
Understanding Brain Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Joana Bicker, Ana Fortuna, Gilberto Alves, Amílcar Falcäo
Drug-induced activation or induction of ABC transporters at the BBB has been less studied compared to efflux inhibition. Nonetheless, there is interest in this field concerning possible induction-mediated DDIs at the BBB and also induction for therapeutic purposes, namely the removal of amyloid-beta peptides from the CNS by P-gp at the BBB [90]. Chan et al. [91] assessed P-gp induction by dexamethasone (ligand of the pregnane X receptor) at the BBB of mice, using quinidine as P-gp substrate. Unbound quinidine concentrations in the brain ISF were 2.5-fold lower, while P-gp expression was 1.5-fold higher in dexamethasone-treated animals compared with vehicle-treated animals [91]. P-gp and BCRP induction has also been studied in human brain microvessel endothelial cells (hCMEC/d3). P-gp expression and function were induced following a 72 h exposure to antiretroviral drugs [92, 93], while selective ligands ofthe peroxisome proliferator-activated receptor alpha (PPAR-α) induced BCRP expression. The intracellular accumulation of mitoxantrone, a BCRP substrate, was significantly reduced after 72 h of exposure to PPAR-a ligands [94]. The upregulation of P-gp/BCRP expression at the BBB has also been reported following chronic exposure to opioids, which may lead to tolerance and pharmacoresistance [95]. Nevertheless, after 11–29 days of treatment of healthy human volunteers with rifampicin, a known P-gp inducer, there was no induction of P-gp at the BBB, using clinical doses which normally induce P-gp in the intestine. It was explained that rifampicin may not achieve sufficient concentrations in BECs to induce P-gp, in contrast to the high concentrations attained in the intestine. Additionally, P-gp at the human BBB may already be maximally induced by environmental or endogenous factors, meaning that further induction may not be feasible [96]. For these reasons, the ITC considers that the induction of efflux transporters at the human BBB appears improbable [89].
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
Based upon their overall architecture, NHRs are grouped into the NR1-NR6 classes (Nuclear Receptors Nomenclature, Committee 1999; Weikum, Liu, and Ortlund 2018). The NHRs most prominently involved in detoxification gene regulation belong to the NR1J groups in C. elegans and Drosophila melanogaster and to the NR1I and H classes in mammals. The latter group includes several NHRs with important roles in detoxification such as: the pregnane X receptor (PXR; also known as the steroid and xenobiotic sensing nuclear receptor, SXR, NR1I2); constitutive androstane receptor (CAR, NR1I3); liver X receptor (LXR, NR1H3), farnesoid X receptor (FXR, NR1H4); and vitamin D receptor (VDR, NR1I1) (Hoffmann and Partridge 2015; Mackowiak and Wang 2016; Oladimeji and Chen 2018). However, other NHRs also regulate detoxification genes in various situations, including the peroxisome proliferator-activated receptors (PPARs) and the Hepatocyte Nuclear Factor 4 (HNF4) type NHRs (Wallace and Redinbo 2013). The latter are especially notable as the C. elegans N2 reference genome features a large group of approximately 265 NHRs that appear to have descended and diversified from an HNF4-like ancestor (Taubert, Ward, and Yamamoto 2011). Most of these remain uncharacterized, but recent studies implicated several as putative xenobiotic response regulating NHRs.