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Journal of Neuropathology and... Mar 2020For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC)...
For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC) transporters which efflux drugs that affect drug exposure and response in the brain. We investigated the expression and cellular distribution of the ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) using immunohistochemistry in spinal cord (SC), motor cortex, and cerebellum from a large cohort of genetically well characterized ALS patients (n = 25) and controls (n = 14). The ALS group included 17 sporadic (sALS) and 8 familial (fALS) patients. Strong P-gp expression was observed in endothelial cells in both control and ALS specimens. Immunohistochemical analysis showed higher P-gp expression in reactive astroglial cells in both gray (ventral horn) and white matter of the SC, as well as in the motor cortex of all ALS patients, as compared with controls. BCRP expression was higher in glia in the SC and in blood vessels and glia in the motor cortex of ALS patients, as compared with controls. P-gp and BCRP immunoreactivity did not differ between sALS and fALS cases. The upregulation of both ABC transporters in the brain may explain multidrug resistance in ALS patients and has implications for the use of both approved and experimental therapeutics.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Adult; Aged; Amyotrophic Lateral Sclerosis; Astrocytes; Cerebellum; Female; Humans; Male; Middle Aged; Motor Cortex; Neoplasm Proteins; Spinal Cord
PubMed: 31999342
DOI: 10.1093/jnen/nlz142 -
European Review For Medical and... May 2023Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a...
Pregnenolone protects the liver against doxorubicin-induced cellular injury by anti-inflammatory, antioxidant, and antiapoptotic mechanisms: role of Keap1/Nrf2/HO-1 and P-glycoprotein.
OBJECTIVE
Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity.
MATERIALS AND METHODS
Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
RESULTS
DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-β1), and mRNA of interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells.
CONCLUSIONS
These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.
Topics: Animals; Male; Rats; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chemical and Drug Induced Liver Injury; Doxorubicin; Heme Oxygenase-1; Interleukin-6; Kelch-Like ECH-Associated Protein 1; Liver; NF-E2-Related Factor 2; Oxidative Stress; Rats, Wistar
PubMed: 37259756
DOI: 10.26355/eurrev_202305_32484 -
Neoplasia (New York, N.Y.) May 2023Multidrug resistance (MDR) hinders treatment efficacy in cancer therapy. One typical mechanism contributing to MDR is the overexpression of permeability-glycoprotein...
Multidrug resistance (MDR) hinders treatment efficacy in cancer therapy. One typical mechanism contributing to MDR is the overexpression of permeability-glycoprotein (P-gp) encoded by ATP-binding cassette subfamily B member 1 (ABCB1). Basic helix-loop-helix family member e40 (BHLHE40) is a well-known transcription factor that has pleiotropic effects including the regulation of cancer-related processes. However, whether BHLHE40 regulates MDR is still unknown. Chromatin immunoprecipitation-seq study revealed BHLHE40 occupancy in the promoter of ABCB1 gene. Adriamycin (ADM)-resistant human chronic myeloid leukemia cells (K562/A) and human breast cancer cells (MCF-7/A) were established. BHLHE40 expression was downregulated in the ADM-resistant cell lines. Overexpression of BHLHE40 resensitized resistant cells to ADM, promoted cell apoptosis in vitro and suppressed tumor growth in vivo, whereas BHLHE40 knockdown induced resistance to ADM in parental cells. Moreover, we found that BHLHE40 regulated drug resistance by directly binding to the ABCB1 promoter (-1605 to -1597) and inactivating its transcription. In consistence, the expression of BHLHE40 was negatively correlated with ABCB1 in various cancer cells, while positively with cancer cell chemosensitivity and better prognosis of patients with breast cancer. The study reveals the role of BHLHE40 as a transcriptional suppressor on the expression of ABCB1, major ABC transporter in chemoresistance. The findings extend the function of BHLHE40 in tumor progression and provides a novel mechanism for the reversal of multidrug resistance.
Topics: Humans; Female; Transcription Factors; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Doxorubicin; Breast Neoplasms; Cell Line, Tumor; Homeodomain Proteins; Basic Helix-Loop-Helix Transcription Factors; ATP Binding Cassette Transporter, Subfamily B
PubMed: 36931039
DOI: 10.1016/j.neo.2023.100891 -
Carbohydrate Polymers Mar 2024Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated...
Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated β-cyclodextrins (β-CD-SHs) as inhibitors of P-gp-mediated efflux in Caco-2 cells. Through a series of transport assays, intracellular accumulation, and efflux of the P-gp substrates Rhodamine 123 (Rh123) and Calcein-AM with and without co-administration of β-CD-SHs were assessed. The results revealed that the cellular uptake of Rh123 and Calcein-AM were enhanced up to 7- and 3-fold, compared to the control, respectively. In efflux studies an up to 2.5-fold reduction of the Rh123 efflux was reached compared the control, indicating a substantial decrease of Rh123 efflux by β-CD-SHs. Furthermore, it was observed that β-CD-SHs led to a decrease in the reactivity of fluorescence-labeled anti-P-gp, suggesting additional effects on the conformation of P-gp. Overall, this study demonstrates the potential of β-CD-SHs as effective modulator of P-gp-mediated drug efflux in Caco-2 cells.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Cyclodextrins; Rhodamine 123
PubMed: 38171673
DOI: 10.1016/j.carbpol.2023.121648 -
Brazilian Journal of Medical and... 2020Diabetes mellitus (DM) has a high prevalence in patients with pancreatic cancer (PaC), but the prognostic value of DM in PaC remains controversial. Alterations of...
Diabetes mellitus (DM) has a high prevalence in patients with pancreatic cancer (PaC), but the prognostic value of DM in PaC remains controversial. Alterations of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) contribute to multidrug resistance and intestinal metabolism in a variety of cancer types, which may be implicated in DM development. This study aimed to explore the potential prognostic value of P-gp and CYP3A4 in PaC patients in the context of DM through long-term follow-up. We retrospectively reviewed the medical records of patients with PaC admitted at The First People's Hospital of Changzhou, Jiangsu, China, from January 2011 to November 2019 and identified two cohorts of adult patients with PaC, including 24 with DM and 24 without DM (non-DM). The baseline clinical characteristics and outcomes were compared. Immunohistochemistry showed that protein expression of P-gp, but not CYP3A, in duodenum tissues was significantly upregulated in PaC patients with DM compared with those without DM. Kaplan-Meier analysis and log-rank test showed that the survival of patients with PaC and DM/high expression of P-gp was not significantly reduced compared with that of patients without DM/low expression of P-gp. These findings suggested that P-gp expression levels were different in the DM and non-DM groups of patients with PaC, but DM and duodenal P-gp levels were not associated with the long-term survival of patients with PaC. It appears that the presence of DM or P-gp expression levels may not serve as effective prognostic markers for PaC.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Aged; Aged, 80 and over; China; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies
PubMed: 33053111
DOI: 10.1590/1414-431X202010168 -
BMC Gastroenterology Jan 2021Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH...
BACKGROUND
Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination.
METHODS
The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed.
RESULTS
Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption.
CONCLUSIONS
Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Caco-2 Cells; Cytochrome P-450 CYP3A; Humans; Hypertension, Portal; Intestinal Absorption; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Octreotide; Rats
PubMed: 33407159
DOI: 10.1186/s12876-020-01532-4 -
International Journal of Molecular... Nov 2022Opioids are widely used in cancer and non-cancer pain management. However, many transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp, ABCB1/MDR1),... (Review)
Review
Opioids are widely used in cancer and non-cancer pain management. However, many transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp, ABCB1/MDR1), may impair their delivery to the brain, thus leading to opioid tolerance. Nonetheless, opioids may regulate P-gp expression, thus altering the transport of other compounds, namely chemotherapeutic agents, resulting in pharmacoresistance. Other kinds of painkillers (e.g., acetaminophen, dexamethasone) and adjuvant drugs used for neuropathic pain may act as P-gp substrates and modulate its expression, thus making pain management challenging. Inflammatory conditions are also believed to upregulate P-gp. The role of P-gp in drug-drug interactions is currently under investigation, since many P-gp substrates may also act as substrates for the cytochrome P450 enzymes, which metabolize a wide range of xenobiotics and endobiotics. Genetic variability of the ABCB1/MDR1 gene may be accountable for inter-individual variation in opioid-induced analgesia. P-gp also plays a role in the management of opioid-induced adverse effects, such as constipation. Peripherally acting mu-opioid receptors antagonists (PAMORAs), such as naloxegol and naldemedine, are substrates of P-gp, which prevent their penetration in the central nervous system. In our review, we explore the interactions between P-gp and opioidergic drugs, with their implications in clinical practice.
Topics: Humans; Analgesics; Analgesics, Opioid; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Tolerance; Pain Management; Palliative Care
PubMed: 36430602
DOI: 10.3390/ijms232214125 -
Epilepsia Open Aug 2022The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several... (Review)
Review
The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE. These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = -60 to -10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Epilepsy; Humans; Neoplasm Proteins; Seizures; Tissue Distribution
PubMed: 34542938
DOI: 10.1002/epi4.12537 -
Drug Metabolism and Pharmacokinetics Apr 2023P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects....
P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects. To date the information on P-gp-mediated drug interaction in lymphocyte is limited. We analyzed the importance on P-gp in lymphocytes using peripheral blood mononuclear cells (PBMCs) together with K562, K562/Adr, and K562/Vin cells, which have various P-gp levels, as cell models, and dexamethasone, nintedanib and apafant as weak to good P-gp substrates. P-gp levels in K562, K562/Adr, and K562/Vin cells were 0.3-, 20-, and 106-fold of healthy PBMCs, respectively. While cell accumulation of apafant and nintedanib decreased in all cells with increasing P-gp levels, dexamethasone accumulation in K562/Adr was comparable to that in healthy PBMCs and K562 cells. Cell accumulations of substrates in cells with low P-gp expression were not significantly changed by the P-gp inhibitors at therapeutic concentrations. However, accumulation increased to 1.4-fold at highest in K562/Adr cells with higher P-gp expression than in PBMCs of the RA patients. These results suggest P-gp controls the cellular concentration of P-gp substrates in PBMCs or K562 cells but cellular concentration of a weak P-gp substrate would not be apparently affected even in cells with a sufficient P-gp expression.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; K562 Cells; Drug Resistance, Multiple; Doxorubicin; Leukocytes, Mononuclear; Drug Resistance, Neoplasm; ATP Binding Cassette Transporter, Subfamily B; Dexamethasone
PubMed: 36724603
DOI: 10.1016/j.dmpk.2022.100487 -
Drug Metabolism and Disposition: the... Oct 2022The placenta is essential for regulating the exchange of solutes between the maternal and fetal circulations. As a result, the placenta offers support and protection to... (Review)
Review
The placenta is essential for regulating the exchange of solutes between the maternal and fetal circulations. As a result, the placenta offers support and protection to the developing fetus by delivering crucial nutrients and removing waste and xenobiotics. ATP-binding cassette transporters, including multidrug resistance protein 1, multidrug resistance-associated proteins, and breast cancer resistance protein, remove chemicals through active efflux and are considered the primary transporters within the placental barrier. Altered transporter expression at the barrier could result in fetal exposure to chemicals and/or accumulation of xenobiotics within trophoblasts. Emerging data demonstrate that expression of these transporters is changed in women with pregnancy complications, suggesting potentially compromised integrity of placental barrier function. The purpose of this review is to summarize the regulation of placental efflux transporters during medical complications of pregnancy, including 1) placental inflammation/infection and chorioamnionitis, 2) hypertensive disorders of pregnancy, 3) metabolic disorders including gestational diabetes and obesity, and 4) fetal growth restriction/altered fetal size for gestational age. For each disorder, we review the basic pathophysiology and consider impacts on the expression and function of placental efflux transporters. Mechanisms of transporter dysregulation and implications for fetal drug and toxicant exposure are discussed. Understanding how transporters are up- or downregulated during pathology is important in assessing possible exposures of the fetus to potentially harmful chemicals in the environment as well as the disposition of novel therapeutics intended to treat placental and fetal diseases. SIGNIFICANCE STATEMENT: Diseases of pregnancy are associated with reduced expression of placental barrier transporters that may impact fetal pharmacotherapy and exposure to dietary and environmental toxicants.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Female; Humans; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Placenta; Pregnancy; Pregnancy Complications; Xenobiotics
PubMed: 34992073
DOI: 10.1124/dmd.121.000449