SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family)

SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) in GtoPdb v.2021.3

The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family) [1]

CATs and HATs: the SLC7 family of amino acid transporters

The SLC7 family is divided into two subgroups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters (the gpaAT family, SLC7A5-11), also called light chains or catalytic chains of the hetero(di)meric amino acid transporters (HAT). The associated glycoproteins (heavy chains) 4F2hc (CD98) or rBAT (D2, NBAT) form the SLC3 family. Members of the CAT family transport essentially cationic amino acids by facilitated diffusion with differential trans-stimulation by intracellular substrates. In some cells, they may regulate the rate of NO synthesis by controlling the uptake of l-arginine as the substrate for nitric oxide synthase (NOS). The heterodimeric amino acid transporters are, in contrast, quite diverse in terms of substrate selectivity and function (mostly) as obligatory exchangers. Their selectivity ranges from large neutral amino acids (system L) to small neutral amino acids (ala, ser, cys-preferring, system asc), negatively charged amino acid (system xc −) and cationic amino acids plus neutral amino acids (system y+L and b0,+-like). Cotransport of Na+ is observed only for the y+L transporters when they carry neutral amino acids. Mutations in b0,+-like and y+L transporters lead to the hereditary diseases cystinuria and lysinuric protein intolerance (LPI), respectivel

Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells

Coadministration of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a pharmacokinetic interaction and a subsequent increase in blood methotrexate concentrations. methotrexate and most NSAIDs are excreted into urine via organic anion transporter 3 (OAT3). The purpose of this study was to evaluate NSAIDs that compete less with methotrexate by using the renal cell line stably expressing human OAT3 (S2-hOAT3) in vitro. We also confirmed the pharmacokinetic interaction of methotrexate with NSAIDs in vivo. [3H]methotrexate uptake into S2-hOAT3 cells was inhibited by most NSAIDs in a concentration-dependent manner, but aspirin, salicylate, tiaramide, and acetaminophen did not inhibit uptake. Inhibition by sulindac and pranoprofen was weaker at therapeutic drug concentrations. Furthermore, methotrexate concentrations in rat serum were significantly increased in a NSAID concentration-dependent manner when concentrations of coadministered NSAIDs increased above the Ki values obtained in the in vitro study. On the other hand, drugs that were not substrates of hOAT3, such as acetaminophen, did not interact with methotrexate. The magnitude of the pharmacokinetic interaction between methotrexate and NSAIDs was significantly correlated with results of the accumulation study in vitro and was not significantly correlated with a reduction of urinary creatinine excretion. In conclusion, methotrexate and most NSAIDs are substrates of hOAT3, and those drugs compete via hOAT3 in tubular secretion, the major mechanism of the interaction between methotrexate and NSAIDs. The accumulation study using S2-hOAT3 cells might be useful for screening of potential interactions between methotrexate and new NSAIDs in vivo

Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans

Purpose: Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs). Methods: Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve. Results: CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14–20 and 2–5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt. Conclusion: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values. © 2017 Springer Science+Business Media New YorkEmbargo Period 12 month

New bleeding model of additives in a polypropylene film under atmospheric pressure

Many additives are commercially used to add more favorable qualities to films. The bleeding process by which the additive in a film comes to the surface is considered. A new bleeding model of additives in a polypropylene film under atmospheric pressure was investigated. Solubility and diffusion are found to be important for explaining this bleeding process. The solubilities and diffusion coefficients of higher fatty acid amides such as erucamide (13-cis-docosenamide) and behenamide (docosanamide) were determined between 40 and 70°C and the difference between the solubilities and the diffusion coefficients was discussed. The experimental results are explained more precisely by assuming two transport processes between the crystalline regions and the amorphous ones. © 2007 Wiley Periodicals, Inc

New bleeding model of additives in a polypropylene film under atmospheric pressure II

金沢大学大学院自然科学研究科出光興産㈱　先進技術研究所　解析技術センター 第二解析技術室Many additives are commercially used to add more favorable qualities to films. The bleeding process by which the additive in a film comes to the surface is considered. A new bleeding model of additives in a polypropylene film under atmospheric pressure was investigated. Solubility and diffusion are found to be important for explaining this bleeding process. It was found that the experimental results were explained more precisely by assuming a twostep transport process between the crystalline regions and the amorphous ones. The solubilities and diffusion coefficients of UV-stabilizers such as 2-(2H-benzotriazol-2-yl)-4(l,l,3,3-tetramethylbutyl)phenol and 2-(2H-benzotriazol-2yl)-4-methylphenol were determined at 4O°C. The difference between the saturation solubilities and the diffusion coefficients of UV-stabilizers was discussed by comparing with the results of molecular dynamics (MD) simulation. © 2007 Wiley Periodicals, Inc

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation

Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function