Oatp1a2

BACKGROUND: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. METHODS: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate...

Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression and function of OATP1A2/2B1. Human embryonic kidney cells expressing OATP1A2 or OATP2B1 (HEK293-OATP1A2/2B1) were exposed to tunicamycin, an N-glycosylation inhibitor, and a plasma membrane fraction (PMF) Western blot assay and an estrone 3-sulfate (E3S) uptake study were conducted...

Zearalenone (ZEN) is a mycoestrogen produced by Fusarium fungi. ZEN is a frequent contaminant in cereal-based products, representing significant health threat. The major reduced metabolites of ZEN are α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL). Since the toxicokinetic interactions of ZEN/ZELs with cytochrome P450 enzymes (CYPs) and organic anion transporting polypeptides (OATPs) have been barely characterized, we examined these interactions applying in vitro models. ZEN and ZELs were relatively strong inhibitors of CYP3A4 and moderate inhibitors of CYP1A2 and CYP2C9...

The present study was conducted to evaluate the effects of dietary garcinol supplementation during late gestation on bile acid metabolism and performance of sows. Sixty sows (Duroc × Yorkshire × Landrace; second- or third-parity; n = 20) with disorder of bile acid metabolism were randomly divided into 3 groups: control diet (CON; basal diet), basal diet with 200 mg garcinol (Low Gar), and basal diet with 600 mg garcinol (High Gar) per kg of feed. The body weight (BW); backfat thickness and litter size of the sows; and birth weight, weaning weight, and mortality of piglets were recorded...

Organic anion transporting polypeptides OATP1A2, OATP1B1, OATP1B3 and OATP2B1 are Na+ - and ATP-independent exchangers of large, organic compounds, encompassing structurally diverse xenobiotics, including various drugs. These OATPs influence intestinal absorption (OATP2B1), hepatic clearance (OATP1B1/3) and blood to brain penetration (OATP1A2, OATP2B1) of their drug substrates. Consequently, OATP-mediated drug or food interactions may lead to altered pharmacokinetics and toxicity. During drug development, investigation of hepatic OATP1B1 and OATP1B3 is recommended by international regulatory agencies...

The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus epithelial (CPE) cells, plays an active role in removing drugs and metabolic wastes from the brain. Recent functional studies in isolated mouse choroid plexus (CP) tissues suggested the existence of organic anion transporting polypeptides (OATPs, encoded by SLCOs) at the apical membrane of BCSFB, which may clear large organic anions from the cerebrospinal fluid (CSF). However, the specific OATP isoform involved is unclear. Using quantitative fluorescence imaging, we showed that the fluorescent anions, sulforhodamine101 (SR101), fluorescein methotrexate (FL-MTX), and 8-fluorescein-cAMP (Fluo-cAMP), are actively transported from the CSF to the subepithelial space in CP tissues isolated from wild-type mice...

Background: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Whilst the role of the efflux transporters are well established in GBM, the expression and function of uptake transporters, such as the organic anion transporting polypeptide (OATP) family, are not well understood. OATPs possess broad substrate specificity that includes anti-cancer agents; therefore, we sought to investigate the expression of four OATP isoforms in human GBM cell types using patient tumor tissue...

OBJECTIVE: Drug transporters are important determinants of drug disposition and response. Tamoxifen is an antiestrogen for breast cancer therapy known for adverse drug reactions (ADRs). In this study, the involvement of OATP transporters in tamoxifen and endoxifen transport was studied in vitro while the impact of single nucleotide variation (SNV) in OATP and efflux transporters P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) on ADRs during tamoxifen therapy were assessed...

OATP1B1 and OATP1B3 are two drug transporters that mediate the uptake of multiple endo- and xenobiotics, including many drugs, into human hepatocytes. Numerous inhibitors have been identified, and for some of them, it is not clear whether they are also substrates. Historically radiolabeled substrates or LC-MS/MS methods were needed to test for transported substrates, both of which can be limiting in time and money. However, the competitive counterflow (CCF) assay originally described for OCT2 and, more recently, for OCT1, OATP2B1, and OATP1A2 does not require radiolabeled substrates or LC-MS/MS methods and, as a result, is a more cost-effective approach to identifying substrates of multidrug transporters...

Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate...

Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser)...

Background: Fetal brain development in the first half of pregnancy is dependent on maternal thyroid hormone (TH), highlighting the importance of trans-placental TH transport. It is yet unclear which transporters are involved in this process. We aimed to identify the major TH transporters in a human placental cell model (BeWo cells). Methods: Messenger RNA expression of the known TH transporters (the monocarboxylate transporter [MCT]8, MCT10, the L-type amino acid transporter [LAT]1, LAT2, the organic anion transporting peptide [OATP]1A2 and OATP4A1) in BeWo cells and human placenta were determined by quantitative PCR...

Green tea (GT) alters the disposition of a number of drugs such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of approximately 300 mg or water (control)...

Resveratrol (RES) is a widely-known natural polyphenol which is also contained by several dietary supplements. Large doses of RES can result in high micromolar levels of its sulfate and glucuronide conjugates in the circulation, due to the high presystemic metabolism of the parent polyphenol. Pharmacokinetic interactions of RES have been extensively studied, while only limited data are available regarding its metabolites. Therefore, in the current study, we examined the interactions of resveratrol-3-sulfate (R3S), resveratrol-3-glucuronide, and dihydroresveratrol (DHR; a metabolite produced by the colon microbiota) with human serum albumin (HSA), cytochrome P450 (CYP) enzymes, and organic anion transporting polypeptides (OATP) employing in vitro models...

The blood-testis barrier (BTB) is formed by basal tight junctions between adjacent Sertoli cells (SCs) of the seminiferous tubules and acts as a physical barrier to protect developing germ cells in the adluminal compartment from reproductive toxicants. Xenobiotics, including antivirals, male contraceptives, and cancer chemotherapeutics, are known to cross the BTB, although the mechanisms that permit barrier circumvention are generally unknown. This study used immunohistological staining of human testicular tissue to determine the site of expression for xenobiotic transporters that facilitate transport across the BTB...

Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which has a specific pharmacological profile. Asciminib has been recently (2021) approved for patients resistant to former TKIs, and because the binding site of this drug (the myristoyl pocket in the ABL1 kinase) is different from that of other TKIs (ATP-binding sites), it is, therefore, effective against T315I mutation of BCR-ABL oncoprotein. All TKIs have a different pharmacological profile due to different chemical structures...

Bisphenol A (BPA) has been shown to exhibit various toxic effects, including the induction of reproductive disorders. Generally, BPA is converted to conjugated metabolites, leading to bio-inactivation. On the other hand, the toxicity of conjugated metabolites is not fully understood. Notably, the placenta develops the sulfate-sulfatase pathway, which transports and reactivates sulfated steroids. Therefore, we investigated the potential adverse effects of the BPA-sulfate conjugate (BPA-S) on human placenta-derived BeWo cytotrophoblasts...

Doxorubicin is a frequently used anticancer drug to treat many types of tumors, such as breast cancer or bronchial carcinoma. The clinical use of doxorubicin is limited by its poorly predictable cardiotoxicity, the reasons of which are so far not fully understood. The drug is a substrate of several efflux transporters such as P-gp or BCRP and was recently reported to be a substrate of cation uptake transporters. To evaluate the potential role of transporter proteins in the accumulation of doxorubicin at its site of action (e...

Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro...

1. OATP1A2 overexpressed is involved in chemotherapy disposition, indicating its role in tumour development and progression.2. CHIP and siRNA were used to evaluate the status of histone acetylation at the OATP1A2 promoter. The role of OATP1A2 was analysed by gene-set enrichment and overall survival analysis.3. OATP1A2 expression levels in ESCC was notably higher than that in para-cancer tissues. OATP1A2 high expression are associated with bile salt metabolic pathway and poor prognosis. Furthermore, HDAC6 was repressed in ESCC, increasing the levels of H3K9Ac catalysed by GCN5/PCAF at the OATP1A2 promoter region...