ABC Family Transporters

Liu, Xiaodong

doi:10.1007/978-981-13-7647-4_2

Cited by 188 publications

(128 citation statements)

References 364 publications

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“…Although this work is largely focused on the transporters of the BBB, P-gp and BCRP are expressed in many human tissues, where they contribute to barrier functions of the body, e.g., testis, retina, and placenta (Liu 2019). Independent of the biological barriers, P-gp and BCRP function in the liver and kidney to remove drugs, harmful toxicants, and metabolites from the body (Leslie et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier

Cannon

Richards

Trexler

et al. 2020

Environ Health Perspect

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BACKGROUND: Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid (GenX) is a replacement for perfluorooctanoic acid in the production of fluoropolymers used in a variety of consumer products. GenX alters fetal development and antibody production and elicits toxic responses in the livers and kidneys of rodents. The GenX effect on the blood-brain barrier (BBB) is unknown. The BBB protects the brain from xenobiotic neurotoxicants and harmful endogenous metabolites. OBJECTIVES: We aimed to investigate the effects of GenX on the transport activity and expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the BBB. METHODS: Transporter activities were measured in isolated rat brain capillaries by a confocal microscopy-based method. ATPase (enzymatic hydrolysis of adenosine triphosphate to inorganic phosphate) levels were measured in vitro. Western blotting determined P-gp and BCRP protein levels. Cell survival after GenX exposure was determined for two human cell lines. RESULTS: Nanomolar levels of GenX inhibited P-gp and BCRP but not MRP2 transport activities in male and female rat brain capillaries. P-gp transport activity returned to control levels after GenX removal. GenX did not reduce P-gp-or BCRP-associated ATPase activity in an in vitro transport assay system. Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor c (PPARc) antagonist. GenX reduced P-gp and BCRP transport activity in human cells. CONCLUSION: In rats, GenX at 0:1-100 nM rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms. PPARc was required for the GenX effects on P-gp but not BCRP transport activity.

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Section: Discussionmentioning

confidence: 99%

Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier

Cannon

Richards

Trexler

et al. 2020

Environ Health Perspect

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“…In fact, there are a variety of factors that are associated with the metabolism of various drugs. For instance, P-gp is an important protein that related to the transport of various drugs and UDP-glucuronosyltransferases were considered to mediate the biotransformation of several xenobiotics, of which the activity also induced changes in the plasma concentration of drugs (Liu 2019b , 2019a ). Therefore, the activity of these proteins and enzymes in the presence of anemarsaponin BII should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Anemarsaponin BII inhibits the activity of CYP3A4, 2D6, and 2E1 with human liver microsomes

Wang

Jiang

Zhou

et al. 2020

Pharmaceutical Biology

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Context Anemarsaponin BII is one of the most active saponins isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), a commonly used Chinese traditional paediatric medicine. Objective This study investigates the effects of anemarsaponin BII on the activity of CYP450s to provide more guidance for the clinical use of anemarsaponin BII. Materials and methods Using various diagnostic substrates, the effects of a fixed concentration of anemarsaponin BII (100 μM) on the activity of eight main isoforms of CYP450s (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6 and 2E1) was first studied with pooled human liver microsomes (HLMs). Then, dose-dependent (0, 2.5, 5, 10, 25, 50 and 100 μM anemarsaponin BII) and time-dependent (0, 5, 10, 15 and 30 min) experiments were performed to obtain corresponding kinetic parameters. Results Anemarsaponin BII showed significant inhibitory effects on the activity of CYP3A4, 2D6 and 2E1 with the IC 50 values of 13.67, 16.26 and 19.72 μM. Anemarsaponin BII acted as a non-competitive inhibitor of CYP3A4 with the K I value of 6.72 μM and competitive inhibitors of CYP2D6 and 2E1 with the K I values of 8.26 and 9.82 μM, respectively. Additionally, the inhibition of CYP3A4 was revealed to be time-dependent with the K I value of 4.88 μM and the K inact value of 0.053/min. Conclusions The inhibitory effect of anemarsaponin BII on the activity of CYP3A4, 2D6 and 2E1 indicated the potential drug–drug interaction between anemarsaponin BII and drugs metabolized by these CYP450s. Further in vivo experiments are needed to validate the potential drug–drug interactions.

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“…Such sgRNAs point to genes whose deficiency enhances drug efficacy and/or toxicity. We first examined the ABC family of drug exporters 40 . Such proteins pump chemicals out of cells, therefore their deficiency will increase cellular drug concentration and result in higher levels of death.…”

Section: Resultsmentioning

confidence: 99%

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

Wei

Yang

et al. 2020

Preprint

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Immunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-19. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs' action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasone's immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.

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ABC Family Transporters

Cited by 188 publications

References 364 publications

Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier

Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier

Anemarsaponin BII inhibits the activity of CYP3A4, 2D6, and 2E1 with human liver microsomes

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

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