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Formulated Natural Selective Estrogen Receptor Modulators: A Key To Restoring Women’s Health
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Plant- and Marine-Based Phytochemicals for Human Health, 2018
A. Anita Margret, S. Aishwarya, J. Theboral
Diets high in lignans may help maintain good cognitive function in postmenopausal women who have anticancer and antiviral effects. They influence gene expression and may protect against estrogen-related diseases such as osteoporosis.42, 65, 82 In postmenopausal women, estrogen deficiency is the major risk factor for osteoporosis. The studies suggest that the mammalian lignans of flax mimic the endogenous estrogens and bind to ERs of bone and hence improve osteocalcin;3 reduce the risk of uterine fibroids in middle-aged women;6 reduce breast cancer risk in women, and reduce the risk of acute fatal coronary events100 and prostate cancer103 in men. SDG is an antioxidant that scavenges hydroxyl ion free radicals.9 Enterolactone activates the pregnane X receptor, which is involved in the metabolism of bile acids, steroid hormones, and has the ability to affect the metabolism of some drugs.39 A study suggested that lignans, along with enterodiol and enterolactone, affect hormone receptors in breast tissue and reduce the risk of breast cancer. They inhibit the activity of aromatase, an enzyme involved in the production of estrogens, and protect against breast cancer.12, 105
Liver, Gallbladder, and Exocrine Pancreas
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Russell C. Cattley, James A. Popp, Steven L. Vonderfecht
While hepatocellular hypertrophy is often associated with ultrastructural and biochemical evidence of enzyme induction, the reverse is not commonly true. Some drugs may induce xenobiotic metabolizing enzymes (phase I [P450 monooxygenases] and/or phase II [conjugating enzymes]) without histological evidence of hypertrophy or ultrastructural (organellar) alterations. In particular, many drugs may induce CYP3A through activation of the pregnane-X-receptor (PXR) without causing significant hypertrophy or ultrastructural alterations (Maronpot et al. 2010). Another example is omeprazole, an atypical AhR-type inducer that increases CYP1A1 but does not cause hepatomegaly or hepatocellular hypertrophy (Kashfi et al. 1995).
Endocrine Disrupting Chemicals, Obesogens, and the Obesity Epidemic
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Raquel Chamorro-Garcia, Bruce Blumberg, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
In the last two decades, there is increasing evidence showing an association between obesogen exposure and cardiovascular disease. Independent cross-sectional and longitudinal epidemiological studies revealed that urine BPA levels in adults is associated with an increasing risk for future coronary artery disease and high blood pressure (Bae et al. 2012, Lang et al. 2008, Melzer et al. 2010, 2012). Ex vivo analyses of rat cardiomyocytes showed that exposure to low doses of BPA alters electrical conduction causing arrhythmias in females; moreover, this effect was exacerbated when other conditions such as stress and previous heart damage were also present (Posnack et al. 2014, Yan et al. 2011, 2013). Two independent experiments showed that chronic BPA exposure in adult mice caused increased blood pressure and atherosclerosis (Saura et al. 2014, Sui et al. 2014), whereas perinatal chronic exposure to low doses of BPA modified the epigenetic profile of cardiac cells, leading to remodeling of cardiac structure and function (Patel et al. 2013). Although the mechanism underlying this phenotype remains unclear, alterations in the activity of the estrogen receptor and the pregnane X receptor are two hypotheses under investigation (Sui et al. 2014, Yan et al. 2013).
Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents
Published in Journal of Dietary Supplements, 2023
Mona H. Haron, Bharathi Avula, Zulfiqar Ali, Amar G. Chittiboyina, Ikhlas A. Khan, Jing Li, Vivian Wang, Charles Wu, Shabana I. Khan
Studies have shown that the effect of drugs on CYP3A4 may be related to activation of human Pregnane X receptor (hPXR) (42–44), which is consistent with our results. To support further on a molecular level, several key ligand-protein, including hydrogen-bonding interactions, were observed between PXR and glabridin/glycycoumarin with the computational mining approach (unpublished data). Nevertheless, for further confirmation of possible effects of licorice extracts and their constituents on drug metabolism, we investigated if an increase in CYP3A4 enzymatic activity, caused by G. glabra, G. uralensis, G. inflata, and two of their most abundant constituents, glabridin, and glycycoumarin, could enhance the metabolism of drugs that are substrates of CYP3A4. For this purpose, we selected two of the most commonly prescribed antiretroviral drugs, dolutegravir and rilpivirine. Our data showed an enhanced metabolism of both drugs in hepatocytes treated with G. glabra and G. uralensis extracts. However, out of the two pure compounds tested, only glycycoumarin caused a considerable increase in drug metabolism. The overall ineffectiveness of glabridin on the metabolism of these drugs could be due to its inhibitory effect on CYP3A4 (12) and the lack of significant induction of CYP3A4 despite strong activation of PXR as observed in the current study.
Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms
Published in Journal of Chemotherapy, 2022
Pregnane X receptor (PXR), categorized as a xenobiotic sensor, part of a protein family of nuclear receptors, gives expressions in the GIT and liver. PXR attaches to different chemical salts, drugs, phytochemicals, and endogenous materials. Sorafenib attaches to PXR and thus switch on the pathway by promoting the execution of downstream genes CYP3A4 and multidrug resistance, which leads to endogenous resistance by HCC cells. Targeting PXR is a useful strategy to assist HCC management [34]. In non-small cell lung cancer, somatic novel CRAF mutation, namely CRAFP261A and CRAFP207S is found in patients. In BEAS-2B lung epithelial cells and HEK293T cells, dimer-dependent activation of the ERK pathway increased upon the expression of CRAFP261A. Depletion of CRAF phosphorylation occurs at the S259 negative regulatory residue. Anchorage-independent growth occurs due to steady expressions of CRAFP261A in BEAS-2B cells and mouse embryonic fibroblasts. Type II RAF inhibitors in BEAS- 2B cells suppress the activities of CRAFP261A-induced ERK pathways. Stronger inhibition and growth cessation are achieved by combined treatment with a MEK inhibitor and type II RAF inhibitors. CRAFP261A mutation acquirement can offer oncogenic characteristics to cells and makes them sensitive to the combined treatment using type II RAF and MEK inhibitors. This mutation must be analyzed in lung and other cancers [35, 36].
Pharmacogenetics-based population pharmacokinetic analysis for dose optimization of ritonavir-boosted atazanavir in Thai adult HIV-infected patients
Published in Expert Review of Clinical Pharmacology, 2022
Noppaket Singkham, Anchalee Avihingsanon, Richard C Brundage, Angela K Birnbaum, Narukjaporn Thammajaruk, Kiat Ruxrungtham, Torsak Bunupuradah, Sasisopin Kiertiburanakul, Ploenchan Chetchotisakd, Baralee Punyawudho
ATV and RTV are mainly metabolized by CYP 3A [3,4]. The CYP3A5 6986 A > G is associated with a decreased enzyme activity and drug clearance [9,10]. Previous studies have shown a lower ATV apparent oral clearance (CL/FATV) [11,12] and higher ATV plasma concentrations [13,14] among patients with CYP3A5 6986 GG compared with AA or AG genotype. Both ATV and RTV are substrates of the P-gp influx transporters, encoded by the ABCB1 gene, play a role in oral bioavailability and drug excretion [15,16]. However, the effect of ABCB1 variants on ATV/RTV pharmacokinetic (PK) remains controversial [17–20]. Some studies show ABCB1 3435 C > T leads to higher intracellular concentrations and lower plasma concentrations of ATV [17,18,20], while ABCB1 2677 G > T exhibits a lower intracellular/plasma concentration ratio of ATV [19]. The OATP1B1 influx transporters, encoded by the SLCO1B1 gene, are responsible for hepatic metabolism and bile excretion of PIs [21,22]. The SCLO1B1 521 T > C was reported to affect ATV and RTV concentrations in Thai patients [14]. Patients with SLCO1B1 521 TC or CC had higher Ctrough of ATV and RTV [14]. The pregnane X receptor (PXR), encoded by NR1I2 gene, regulates the expression of metabolic enzymes and transport proteins often leading to upregulation [22]. The NR1I2 63396 C > T was related to lower ATV Ctrough [23] and higher CL/FATV [24].