Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.

BACKGROUND: Solute carrier (SLC) transporters, a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment (TME). Amino acids are fundamental building blocks of cells and play essential roles in protein synthesis, nutrient sensing, and oncogenic signaling pathways. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. SCOPE OF REVIEW: In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. MAJOR CONCLUSIONS: Amino acids transportation by SLCs plays a critical role in tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although several studies evaluated the function of SLC7A11 and SLC1A5, the role of some SLC proteins in cancer is not studied well. To exert their functions, SLCs mediate metabolic rewiring, regulate the maintenance of redox balance, affect main oncogenic pathways, regulate amino acids bioavailability within the TME, and alter the sensitivity of cancer cells to therapeutics. However, different therapeutic methods that prevent the function of SLCs were able to inhibit tumor progression. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids and their transporters within the SLC superfamily.

Multi-omics analysis reveals the association between specific solute carrier proteins gene expression patterns and the immune suppressive microenvironment in glioma.

Glioma is the most prevalent malignant brain tumour. Currently, reshaping its tumour microenvironment has emerged as an appealing strategy to enhance therapeutic efficacy. As the largest group of transmembrane transport proteins, solute carrier proteins (SLCs) are responsible for the transmembrane transport of various metabolites and ions. They play a crucial role in regulating the metabolism and functions of malignant cells and immune cells within the tumour microenvironment, making them a promising target in cancer therapy. Through multidimensional data analysis and experimental validation, we investigated the genetic landscape of SLCs in glioma. We established a classification system comprising 7-SLCs to predict the prognosis of glioma patients and their potential responses to immunotherapy and chemotherapy. Our findings unveiled specific SLC expression patterns and their correlation with the immune-suppressive microenvironment and metabolic status. The 7-SLC classification system was validated in distinguishing subgroups within the microenvironment, specifically identifying subsets involving malignant cells and tumour-associated macrophages. Furthermore, the orphan protein SLC43A3, a core member of the 7-SLC classification system, was identified as a key facilitator of tumour cell proliferation and migration, suggesting its potential as a novel target for cancer therapy.

Systematic in silico discovery of novel solute carrier-like proteins from proteomes.

Solute carrier (SLC) proteins represent the largest superfamily of transmembrane transporters. While many of them play key biological roles, their systematic analysis has been hampered by their functional and structural heterogeneity. Based on available nomenclature systems, we hypothesized that many as yet unidentified SLC transporters exist in the human genome, which await further systematic analysis. Here, we present criteria for defining "SLC-likeness" to curate a set of "SLC-like" protein families from the Transporter Classification Database (TCDB) and Protein families (Pfam) databases. Computational sequence similarity searches surprisingly identified ~120 more proteins in human with potential SLC-like properties compared to previous annotations. Interestingly, several of these have documented transport activity in the scientific literature. To complete the overview of the "SLC-ome", we present an algorithm to classify SLC-like proteins into protein families, investigating their known functions and evolutionary relationships to similar proteins from 6 other clinically relevant experimental organisms, and pinpoint structural orphans. We envision that our work will serve as a stepping stone for future studies of the biological function and the identification of the natural substrates of the many under-explored SLC transporters, as well as for the development of new therapeutic applications, including strategies for personalized medicine and drug delivery.

A phylogenetic analysis between humans and D. melanogaster: A repertoire of solute carriers in humans and flies.

The solute carrier (SLC) superfamily is the largest group of transporters in humans, with the role to transport solutes across plasma membranes. The SLCs are currently divided into 65 families with 430 members. Here, we performed a detailed mining of the SLC superfamily and the recent annotated family of "atypical" SLCs in human and D. melanogaster using Hidden Markov Models and PSI-BLAST. Our analyses identified 381 protein sequences in D. melanogaster and of those, 55 proteins have not been previously identified in flies. In total, 11 of the 65 human SLC families were found to not be conserved in flies, while a few families are highly conserved, which perhaps reflects the families' functions and roles in cellular pathways. This study provides the first collection of all SLC sequences in D. melanogaster and can serve as a SLC database to be used for classification of SLCs in other phyla.

SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.

The uptake and efflux of solutes across a plasma membrane is controlled by transporters. There are two main superfamilies of transporters, adenosine 5'-triphosphate (ATP) binding cassettes (ABCs) and solute carriers (SLCs). In the brain, SLC transporters are involved in transporting various solutes across the blood-brain barrier, blood-cerebrospinal fluid barrier, astrocytes, neurons, and other brain cell types including oligodendrocytes and microglial cells. SLCs play an important role in maintaining normal brain function. Hence, mutations in the genes that encode SLC transporters can cause a variety of neurological disorders. We identified the following SLC gene variants in 25 patients in our cohort: SLC1A2, SLC2A1, SLC5A1, SLC6A3, SLC6A5, SLC6A8, SLC9A6, SLC9A9, SLC12A6, SLC13A5, SLC16A1, SLC17A5, SLC19A3, SLC25A12, SLC25A15, SLC27A4, SLC45A1, SLC46A1, and SLC52A3. Eight patients harbored pathogenic or likely pathogenic mutations (SLC5A1, SLC9A6, SLC12A6, SLC16A1, SLC19A3, and SLC52A3), and 12 patients were found to have variants of unknown clinical significance (VOUS); these variants occurred in 11 genes (SLC1A2, SLC2A1, SLC6A3, SLC6A5, SLC6A8, SLC9A6, SLC9A9, SLC13A5, SLC25A12, SLC27A4, and SLC45A1). Five patients were excluded as they were carriers. In the remaining 20 patients with SLC gene variants, we identified 16 possible distinct neurological disorders. Based on the clinical presentation, we categorized them into genes causing intellectual delay (ID) or autism spectrum disorder (ASD), those causing epilepsy, those causing vitamin-related disorders, and those causing other neurological diseases. Several variants were detected that indicated possible personalized therapies: SLC2A1 led to dystonia or epilepsy, which can be treated with a ketogenic diet; SLC6A3 led to infantile parkinsonism-dystonia 1, which can be treated with levodopa; SLC6A5 led to hyperekplexia 3, for which unnecessary treatment with antiepileptic drugs should be avoided; SLC6A8 led to creatine deficiency syndrome type 1, which can be treated with creatine monohydrate; SLC16A1 led to monocarboxylate transporter 1 deficiency, which causes seizures that should not be treated with a ketogenic diet; SLC19A3 led to biotin-thiamine-responsive basal ganglia disease, which can be treated with biotin and thiamine; and SLC52A3 led to Brown-Vialetto-Van-Laere syndrome 1, which can be treated with riboflavin. The present study examines the prevalence of SLC gene mutations in our cohort of children with epilepsy and other neurological disorders. It highlights the diverse phenotypes associated with mutations in this large family of SLC transporter proteins, and an opportunity for personalized genomics and personalized therapeutics.

Ontogeny of renal, hepatic, and placental expression of ATP-binding cassette and solute carrier transporters in the rat and the rabbit.

Species differences in developmental toxicity can be due to varying expression of xenobiotic transporters. Hence, knowledge on the ontogeny of these transporters, especially in human, rat and rabbit, is pivotal. Two superfamilies of transporters, the ATP-binding cassette (ABC) and the solute carrier (SLC) transporters, are well known for their role in the absorption, distribution and/or elimination of xenobiotics and endogenous substances. The aim of this study was to compare the expression levels of these xenobiotic transporters in liver, kidney and placenta of man, Wistar rat and New Zealand White rabbit during pre- and postnatal development. For this purpose, qPCR experiments were performed for rat and rabbit tissues and the gene expression profiles were compared with literature data from man, rat and rabbit. Data analysis showed large differences in transporter expression in development and between species. These results can be used to better understand developmental toxicity findings in non-clinical species and their relevance for man.

Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin.

Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.

Reduced Expression of Slc Genes in the VTA and NAcc of Male Mice with Positive Fighting Experience.

A range of several psychiatric medications targeting the activity of solute carrier (SLC) transporters have proved effective for treatment. Therefore, further research is needed to elucidate the expression profiles of the Slc genes, which may serve as markers of altered brain metabolic processes and neurotransmitter activities in psychoneurological disorders. We studied the Slc differentially expressed genes (DEGs) using transcriptomic profiles in the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of control and aggressive male mice with psychosis-like behavior induced by repeated experience of aggression accompanied with wins in daily agonistic interactions. The majority of the Slc DEGs were shown to have brain region-specific expression profiles. Most of these genes in the VTA and NAcc (12 of 17 and 25 of 26, respectively) were downregulated, which was not the case in the PFC (6 and 5, up- and downregulated, respectively). In the VTA and NAcc, altered expression was observed for the genes encoding the transporters of neurotransmitters as well as inorganic and organic ions, amino acids, metals, glucose, etc. This indicates an alteration in transport functions for many substrates, which can lead to the downregulation or even disruption of cellular and neurotransmitter processes in the VTA and NAcc, which are attributable to chronic stimulation of the reward systems induced by positive fighting experience. There is not a single Slc DEG common to all three brain regions. Our findings show that in male mice with repeated experience of aggression, altered activity of neurotransmitter systems leads to a restructuring of metabolic and neurotransmitter processes in a way specific for each brain region. We assume that the scoring of Slc DEGs by the largest instances of significant expression co-variation with other genes may outline a candidate for new prognostic drug targets. Thus, we propose that the Slc genes set may be treated as a sensitive genes marker scaffold in brain RNA-Seq studies.

Loss of the mitochondrial phosphate carrier SLC25A3 induces remodeling of the cardiac mitochondrial protein acylome.

Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased posttranslational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel cross talk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.

Welcome to the Family: Identification of the NAD+ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25.

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD+ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD+ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD+ carrier in mammals, a long-standing mystery in NAD+ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.

"SLC-omics" of the kidney: solute transporters along the nephron.

The fluid in the 14 distinct segments of the renal tubule undergoes sequential transport processes that gradually convert the glomerular filtrate into the final urine. The solute carrier (SLC) family of proteins is responsible for much of the transport of ions and organic molecules along the renal tubule. In addition, some SLC family proteins mediate housekeeping functions by transporting substrates for metabolism. Here, we have developed a curated list of SLC family proteins. We used the list to produce resource webpages that map these proteins and their transcripts to specific segments along the renal tubule. The data were used to highlight some interesting features of expression along the renal tubule including sex-specific expression in the proximal tubule and the role of accessory proteins (ß-subunit proteins) that are thought to be important for polarized targeting in renal tubule epithelia. Also, as an example of application of the data resource, we describe the patterns of acid-base transporter expression along the renal tubule.

Antiretroviral Drug Transporters and Metabolic Enzymes in Circulating Monocytes and Monocyte-Derived Macrophages of ART-Treated People Living With HIV and HIV-Uninfected Individuals.

ABSTRACT: Membrane-associated drug transport proteins and drug metabolic enzymes could regulate intracellular antiretroviral (ARV) drug concentrations in HIV-1 target cells such as myeloid cells. We investigated the expression of these transporters and enzymes in monocyte subsets and monocyte-derived macrophages (MDMs) isolated from peripheral blood mononuclear cells (PBMCs) of HIV-uninfected individuals (HIV-negative) and people living with HIV receiving viral suppressive antiretroviral therapy (ART; HIV+ART) and examined plasma and intracellular ARV concentrations. Monocytes were isolated from PBMCs of 12 HIV-negative and 12 HIV+ART donors and differentiated into MDMs. The mRNA and protein expression of drug transporters and metabolic enzymes were analyzed by quantitative real-time polymerase chain reaction and flow cytometry, respectively. ARV drug concentrations were quantified in plasma, PBMCs, monocytes, and MDMs by LC-MS/MS. The mRNA expression of relevant ARV transporters or metabolic enzymes, ABCB1/P-gp, ABCG2/BCRP, ABCC1/MRP1, ABCC4/MRP4, SLC22A1/OCT1, SLC29A2/ENT2, CYP2B6, CYP2D6, and UGT1A1, was demonstrated in monocytes and MDMs of 2 to 4 HIV-negative donors. P-gp, BCRP, and MRP1 proteins were differentially expressed in classical, intermediate, and nonclassical monocytes and MDMs of both HIV+ART and HIV-negative donors. Intracellular concentrations of ARVs known to be substrates of these transporters and metabolic enzymes were detected in monocytes of HIV+ART donors but were undetectable in MDMs. In this study, we demonstrated the expression of drug transporters and metabolic enzymes in monocytes and MDMs of HIV-negative and HIV+ART individuals, which could potentially limit intracellular concentrations of ARVs and contribute to residual HIV replication. Further work is needed to assess the role of these transporters in the penetration of ARVs in tissue macrophages.

Genome Evolutionary Dynamics Meets Functional Genomics: A Case Story on the Identification of SLC25A44.

Gene clusters are becoming promising tools for gene identification. The study reveals the purposive genomic distribution of genes toward higher inheritance rates of intact metabolic pathways/phenotypes and, thereby, higher fitness. The co-localization of co-expressed, co-interacting, and functionally related genes was found as genome-wide trends in humans, mouse, golden eagle, rice fish, Drosophila, peanut, and Arabidopsis. As anticipated, the analyses verified the co-segregation of co-localized events. A negative correlation was notable between the likelihood of co-localization events and the inter-loci distances. The evolution of genomic blocks was also found convergent and uniform along the chromosomal arms. Calling a genomic block responsible for adjacent metabolic reactions is therefore recommended for identification of candidate genes and interpretation of cellular functions. As a case story, a function in the metabolism of energy and secondary metabolites was proposed for Slc25A44, based on its genomic local information. Slc25A44 was further characterized as an essential housekeeping gene which has been under evolutionary purifying pressure and belongs to the phylogenetic ETC-clade of SLC25s. Pathway enrichment mapped the Slc25A44s to the energy metabolism. The expression of peanut and human Slc25A44s in oocytes and Saccharomyces cerevisiae strains confirmed the transport of common precursors for secondary metabolites and ubiquinone. These results suggest that SLC25A44 is a mitochondrion-ER-nucleus zone transporter with biotechnological applications. Finally, a conserved three-amino acid signature on the cytosolic face of transport cavity was found important for rational engineering of SLC25s.

Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states.

Metabolism negotiates cell-endogenous requirements of energy, nutrients and building blocks with the immediate environment to enable various processes, including growth and differentiation. While there is an increasing number of examples of crosstalk between metabolism and chromatin, few involve uptake of exogenous metabolites. Solute carriers (SLCs) represent the largest group of transporters in the human genome and are responsible for the transport of a wide variety of substrates, including nutrients and metabolites. We aimed to investigate the possible involvement of SLC-mediated solutes uptake and cellular metabolism in regulating cellular epigenetic states. Here, we perform a CRISPR-Cas9 transporter-focused genetic screen and a metabolic compound library screen for the regulation of BRD4-dependent chromatin states in human myeloid leukaemia cells. Intersection of the two orthogonal approaches reveal that loss of transporters involved with purine transport or inhibition of de novo purine synthesis lead to dysfunction of BRD4-dependent transcriptional regulation. Through mechanistic characterization of the metabolic circuitry, we elucidate the convergence of SLC-mediated purine uptake and de novo purine synthesis on BRD4-chromatin occupancy. Moreover, adenine-related metabolite supplementation effectively restores BRD4 functionality on purine impairment. Our study highlights the specific role of purine/adenine metabolism in modulating BRD4-dependent epigenetic states.

Single-cell mRNA profiling reveals changes in solute carrier expression and suggests a metabolic switch during zebrafish pronephros development.

Developing organisms need to adapt to environmental variations as well as to rapid changes in substrate availability and energy demands imposed by fast-growing tissues and organs. Little is known about the adjustments that kidneys undergo in response to these challenges. We performed single-cell RNA sequencing of zebrafish pronephric duct cells to understand how the developing kidney responds to changes in filtered substrates and intrinsic energy requirements. We found high levels of glucose transporters early in development and increased expression of monocarboxylate transporters at later times. This indicates that the zebrafish embryonic kidney displays a high glucose transporting capacity during early development, which is replaced by the ability to absorb monocarboxylates and amino acids at later stages. This change in transport capacity was accompanied by the upregulation of mitochondrial carriers, indicating a switch to increased oxidative phosphorylation to meet the increasing energy demand of a developing kidney.NEW & NOTEWORTHY The zebrafish embryonic kidney has high levels of glucose transporters during early development, which are replaced by monocarboxylate and amino acid transporters later on. Inhibition of Na+-glucose cotransporter-dependent glucose transport by sotagliflozin also increased slc2a1a expression, supporting the idea that the glucose transport capacity is dynamically adjusted during zebrafish pronephros development. Concurrent upregulation of mitochondrial SCL25 transporters at later stages supports the idea that the pronephros adjusts to changing substrate supplies and/or energy demands during embryonic development.

The GBA-370Rec Parkinson's disease risk haplotype harbors a potentially pathogenic variant in the mitochondrial gene SLC25A44.

GBA variations are common risk factors for Parkinson's disease (PD), and are found in 21.7% of Ashkenazi PD patients (AJ-PD), 4.23% of them carry an allele, 370Rec, which is different from the common GBA-N370S allele. Using whole-genome-sequencing of 370Rec carriers, N370S carriers, and non-carriers, we characterize the unique 370Rec haplotype in AJ-PDs, and show that it harbors a missense variant replacing the highly conserved methionine-27 with valine in the transmembrane domain of the mitochondrial SLC25A44.

Mutation analysis of seven SLC family transporters for early-onset Parkinson's disease in Chinese population.

The solute carrier (SLC) transporters have been suggested to play important roles in neurodegenerative disorders. Recently, seven SLC transporters were identified to be associated with Parkinson's disease (PD) by genome-wide association studies. However, few replications were conducted, and whether rare variants in these genes were associated with PD was not explored yet. To elucidate the genetic associations of these SLCs with PD, we investigated the rare variants in 743 Chinese early-onset PD (EOPD) patients using whole-exome sequencing, and evaluated the association between rare variants and PD at allele and gene levels. Totally, 58 rare variants were identified in SLC50A1, SLC41A1, SLC45A3, SLC44A4, SLC56A2, SLC2A13 and SLC38A1. At allele level, 6 variants were nominally associated with PD, namely p.S423G in SLC45A3, p.I551V, p.T435S, p.R323C and p.V101M in SLC2A13, and p.R285Q in SLC41A1. Gene-based burden analysis showed enrichment of rare variants of SLC2A13 in EOPD. Our study systematically analyzed the genetic involvement of SLCs in EOPD, identified SLC2A13 as a risk gene for PD, and broadened the current mutation spectrum of PD.

Variants in FLRT3 and SLC35E2B identified using exome sequencing in seven high myopia families from Central Europe.

PURPOSE: High myopia (HM) is an eye disorder with both environmental and genetic factors involved. Many genetic factors responsible for HM were recognized worldwide, but little is known about genetic variants underlying HM in Central Europe. Thus, the aim of this study was to identify rare sequence variants involved in HM in families from Central Europe to better understand the genetic basis of HM. MATERIALS AND METHODS: We assessed 17 individuals from 7 unrelated Central European families with hereditary HM using exome sequencing (ES). Segregation of selected variants in other available family members was performed using Sanger sequencing. RESULTS: Detected 73 rare variants were selected for verification. We observed 2 missense variants, c.938C>T in SLC35E2B - encoding solute carrier family 35 member E2B, and c.1642G>C in FLRT3 - encoding fibronectin leucine rich transmembrane protein, segregating with HM in one family. CONCLUSIONS: FLRT3 â€‹and/or â€‹SLC35E2B â€‹could represent disease candidate genes and identified sequence variants might be responsible for HM in the studied family.

Circadian regulation of transporter expression and implications for drug disposition.

Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity.Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed.Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.

Role for Drug Transporters in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity to widely used chemotherapeutics. Although the exact molecular mechanism of chemotherapy-induced peripheral neuropathy remains elusive, there is consensus that it is caused by damage to the peripheral nervous system leading to sensory symptoms. Recently developed methodologies have provided evidence of expression of drug transporters in the peripheral nervous system. In this literature review, we explore the role for drug transporters in CIPN. First, we assessed the transport of chemotherapeutics that cause CIPN (taxanes, platins, vincristine, bortezomib, epothilones, and thalidomide). Second, we cross-referenced the transporters implicated in genetic or functional studies with CIPN with their expression in the peripheral nervous system. Several drug transporters are involved in the transport of chemotherapeutics that cause peripheral neuropathy and particularly efflux transporters, such as ABCB1 and ABCC1, are expressed in the peripheral nervous system. Previous literature has linked genetic variants in efflux transporters to higher risk of peripheral neuropathy with the taxanes paclitaxel and docetaxel and the vinca alkaloid vincristine. We propose that this might be due to accumulation of the chemotherapeutics in the peripheral nervous system due to reduced neuronal efflux capacity. Thus, concomitant administration of efflux transporter inhibitors may lead to higher risk of adverse events of drugs that cause CIPN. This might prove valuable in drug development where screening new drugs for neurotoxicity might also require drug transporter consideration. There are ongoing efforts targeting drug transporters in the peripheral nervous system to reduce intraneuronal concentrations of chemotherapeutics that cause CIPN, which might ultimately protect against this dose-limiting adverse event.