ABCC Subfamily Research Articles

I-CBP112 declines overexpression of ATP-binding cassette transporters and sensitized drug-resistant MDA-MB-231 and A549 cell lines to chemotherapy drugs

Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may develop resistance to chemotherapeutics in time due to inter alia overexpression of ATP-binding cassette transporters. Using clinically-relevant resistant models of triple negative breast cancer (MDA-MB-231; TNBC) as well as non-small cell lung cancer (A549; NSCLC), we tested the efficacy of I-CBP112 – CBP/EP300 bromodomain inhibitor to overcome drug resistance by declining ABC gene transcription. I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures. This was phenocopied only by the joint effect of ABC inhibitors such as tariquidar (ABCB1 – P-glycoprotein and ABCG2) and MK-571 (ABCC), whereas single inhibition of ABCB1/ABCG2 or ABCC proteins did not affect drug accumulation, thereby implying the need of simultaneous deficiency in activity of majority of drug pumps for enhanced drug retention. I-CBP112 failed to directly inhibit activity of ABCB1, ABCG2 and ABCC subfamily members at the same time. Importantly, I-CBP112 treated cancer cells polarized human macrophages into proinflammatory phenotypes. Moreover, I-CBP112 remained non-toxic to primary cell lines, nor did it enhance anticancer drug toxicity to blood-immune cells. In silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.

Activity of Lysosomal ABCC3, ABCC5 and ABCC10 is Responsible for Lysosomal Sequestration of Doxorubicin and Paclitaxel-Oregongreen488 in Paclitaxel-Resistant Cancer Cell Lines.

Cancer cell multidrug resistance induced by paclitaxel contributes to the high failure rates of chemotherapy and relapse of the disease. Several mechanisms have been described that underlie the observed resistance, including the overexpression of ABCB1 (P-glycoprotein), which represents an ATP-binding cassette (ABC) transmembrane protein, and its functional occurrence in lysosomal membranes is linked to drug accumulation in these organelles. Using clinically-relevant models of paclitaxel-resistant triple-negative breast cancer and non-small cell lung cancer cell lines, we provide evidence for the role of ABCC subfamily members in the lysosomal sequestration of drugs in multidrug resistant phenotypes. Proteins expression level and its cellular localisation was measured using Western Blot and confocal microscopy. Drug accumulation was analysed by confocal microscopy and flow cytometry. Drug cytotoxicity was tested using resasurin assay and anexin V propidium iodide staining. Regardless of the alteration in gene expression, paclitaxel induced the intracellular redistribution of ABCC3, ABCC5 and ABCC10 and their enrichment in lysosomes. The use of ABCC inhibitors and transient silencing of these three genes limited the accumulation of doxorubicin and paclitaxel-OregonGreen488 in lysosomes, while having little impact on the total drug level inside cells. The cancer cells were also sensitized to various structurally unrelated chemotherapeutics of differing acidity. The results suggest that lysosome membranes anchored ABCC proteins which remained functionally active and were capable to load chemotherapeutics into lysosomes in paclitaxel-resistant cancer cells. Therefore, targeting of lysosomal ABCC transporters may help to overcome paclitaxel-induced resistance by reducing the accumulation of drugs in lysosomes.

Genome-Wide Identification of ATP-Binding Cassette (ABC) Transporter Provides Insight to Genes Related to Anthocyanin Transportation in New Teinturier Grape Germplasm ‘ZhongShan-HongYu’

ATP-binding cassette (ABC) transporters are a large class of superfamily involved in a variety of biological processes with multiple functions, including phytohormone transport, heavy metal ion detoxification, and so on. Anthocyanin pigmentation in grapes is a commercially important feature of this superfamily. To elucidate the mechanisms of the VvABC gene at different stages in grape berries, we analyzed and characterized the ABC family in ‘ZhongShan-HongYu’ (ZS-HY) berries using RNA-seq analysis. In this study, a total of 146 VvABC genes were identified by comprehensive bioinformatics analysis, which outlined their gene structure, chromosomal location, conserved domains, phylogenetic relationships, and collinearity analysis. The VvABC family could be divided into eight subfamilies based on the phylogenetic analysis. Fifty-eight VvABC genes were identified from the RNA-seq data, of which 31 belong to the ABCG subfamily, 15 belong to the ABCC subfamily, 8 belong to the ABCB subfamily, 2 belong to the ABCF subfamily, and only 1 belongs to each of the ABCA and ABCD subfamilies. We used qRT-PCR to detect the expression of VvABC genes in different organs and found that it changed significantly in different organs. Phylogenetic analysis showed that genes involved in anthocyanin transport in other species were closely related to members of the ABCC subfamily. Subsequently, analysis of the promoter elements and the protein interactions of the VvABCC genes using RNA-seq was performed. This study has improved our understanding of the functions of the ABC gene family and provided a basis for the role of ABC genes in grape anthocyanin transport.

Morphological and Physiological Indicators and Transcriptome Analyses Reveal the Mechanism of Selenium Multilevel Mitigation of Cadmium Damage in Brassica juncea.

Cadmium (Cd) is a common agricultural soil pollutant, which does serious harm to the environment and the human body. In this study, Brassica juncea was treated with different concentrations of CdCl2 and Na2SeO3. Then, physiological indexes and transcriptome were measured to reveal the mechanisms by which Se reduces the inhibition and toxicity of Cd in B. juncea. The results showed that Se alleviated the inhibitive Cd effects on seedling biomass, root length, and chlorophyll, and promoted the adsorption of Cd by pectin and lignin in the root cell wall (CW). Se also alleviated the oxidative stress induced by Cd, and reduced the content of MDA in cells. As a result, SeCys and SeMet alleviated the transport of Cd to the shoots. Transcriptome data showed that the bivalent cation transporter MPP and ABCC subfamily participated in the separation of Cd in vacuoles, CAL1 was related to the chelation of Cd in the cytoplasm of cells, and ZIP transporter 4 reduced the transport of Cd to the shoots. These results indicated that Se alleviated the damage of Cd in plants and decreased its transport to the shoots by improving the antioxidant system, enhancing the ability of the CW to adsorb Cd, reducing the activity of Cd transporters, and chelating Cd.

Expression profile of the entire detoxification gene inventory of the western honeybee, Apis mellifera across life stages

The western honeybee, Apis mellifera, is a managed pollinator of many crops and potentially exposed to a wide range of foreign compounds, including pesticides throughout its life cycle. Honeybees as well as other insects recruit molecular defense mechanisms to facilitate the detoxification of xenobiotic compounds. The inventory of detoxification genes (DETOXome) is comprised of five protein superfamilies: cytochrome P450 monooxygenases (P450), carboxylesterases, glutathione S-transferases (GST), UDP-glycosyl transferases (UGT) and ATP-binding cassette (ABC) transporters. Here we characterized the gene expression profile of the entire honeybee DETOXome by analyzing 47 transcriptomes across the honeybee life cycle, including different larval instars, pupae, and adults. All life stages were well separated by principal component analysis, and K-means clustering revealed distinct temporal patterns of gene expression. Indeed, >50% of the honeybee detoxification gene inventory is found in one cluster and follows strikingly similar expression profiles, i.e., increased expression during larval development, followed by a sharp decline after pupation and a steep increase again in adults. This cluster includes 29 P450 genes dominated by CYP3 and CYP4 clan members, 15 ABC transporter genes mostly belonging to the ABCC subfamily and 13 carboxylesterase genes including almost all members involved in dietary/detox and hormone/semiochemical processing. RT-qPCR analysis of selected detoxification genes from all families revealed high expression levels in various tissues, especially Malpighian tubules, fatbody and midgut, supporting the view that these tissues are essential for metabolic clearance of environmental toxins and pollutants in honeybees. Our study is meant to spark further research on the molecular basis of detoxification in this critical pollinator to better understand and evaluate negative impacts from potentially toxic substances. Additionally, the entire gene set of 47 transcriptomes collected and analyzed provides a valuable resource for future honeybee research across different disciplines.

Genome-scale analysis of ABC transporter genes and characterization of the ABCC type transporter genes in the oriental armyworm, Mythimna separata (Walker)

The oriental armyworm Mythimna separata is a polyphagous, migratory corn pest in China and other Asian countries. Transgenic Bacillus thuringiensis (Bt) corn may effectively control this insect pest. Several reports have suggested that ATP-binding cassette (ABC) transporter proteins may act as receptors that bind Bt toxins. However, our knowledge about ABC transporter proteins in M. separata is limited. We identified 43 ABC transporter genes in the M. separata genome by bioinformatics prediction. Evolutionary tree analysis grouped these 43 genes into 8 subfamilies, ABCA to ABCH. Among the 13 ABCC subfamily genes, the transcript levels of MsABCC2 and MsABCC3 were upregulated. In addition, RT-qPCR analyses of these two potentials showed that both were predominantly expressed in the midgut tissue. Knock-down of MsABCC2, but not MsABCC3, decreased Cry1Ac susceptibility as indicated by increased larval weight and reduced larval mortality. This suggested that MsABCC2 might play a more important role in Cry1Ac toxicity and that it is a putative Cry1Ac receptor in M. separata. Together, these findings provide unique and valuable information for future elucidating of the role of ABC transporter genes in M. separata, which is highly valuable and important for the long-term application of Bt insecticidal protein.

Effect of Nano-Selenium on Nutritional Quality of Cowpea and Response of ABCC Transporter Family.

It is an important way for healthy Selenium (Se) supplement to transform exogenous Se into organic Se through crops. In the present study, Vigna unguiculata was selected as a test material and sprayed with biological nano selenium (SeNPs) and Na2SeO3, and its nutrient composition, antioxidant capacity, total Se and organic Se content were determined, respectively. Further, the response of ABC transporter family members in cowpea to different exogenous Se treatments was analyzed by transcriptome sequencing combined with different Se forms. The results show that the soluble protein content of cowpea increased after twice Se treatment. SeNPs treatment increased the content of cellulose in cowpea pods. Na2SeO3 treatment increased the content of vitamin C (Vc) in cowpea pods. Se treatments could significantly increase the activities of Peroxidase (POD), polyphenol oxidase (PPO) and catalase (CAT) in cowpea pods and effectively maintain the activity of Superoxide dismutase (SOD). SeNPs can reduce the content of malondialdehyde (MDA) in pods. After Se treatment, cowpea pods showed a dose-effect relationship on the absorption and accumulation of total Se, and Na2SeO3 treatment had a better effect on the increase of total Se content in cowpea pods. After treatment with SeNPs and Na2SeO3, the Se species detected in cowpea pods was mainly SeMet, followed by MeSeCys. Inorganic Se can only be detected in the high concentration treatment group. Analysis of transcriptome data of cowpea treated with Se showed that ABC transporters could play an active role in response to Se stress and Se absorption, among which ABCB, ABCC and ABCG subfamilies played a major role in Se absorption and transportation in cowpea. Further analysis by weighted gene co-expression network analysis (WGCNA) showed that the content of organic Se in cowpea treated with high concentration of SeNPs was significantly and positively correlated with the expression level of three transporters ABCC11, ABCC13 and ABCC10, which means that the ABCC subfamily may be more involved in the transmembrane transport of organic Se in cells.

Genome-wide identification of Oryza sativa: A new insight for advanced analysis of ABC transporter genes associated with the degradation of four pesticides

ATP-binding cassette (ABC) transporter is a large genes superfamily. It involves transportation of diverse substrates (e.g., heavy metal, amino acids, pesticides, metabolites). The ABC transporters can be strongly induced by environmental stress and responsible for the phase III metabolic process of toxic compounds in plants. To investigate the potential molecular and biochemical function of ABC transporters in response to pesticides, we used bioinformatics and high-throughput sequencing to identify 107 loci from rice (Oryza sativa) exposed to different pesticides (ametryn, AME; bentazone, BNTZ; fomesafen, FSA; mesotrione, MTR) and annotated as ABC transporter genes. ABC transporter genes were categorized to eight subfamilies including ABCA-G and ABCI. ABCG subfamily was the largest group in rice genome followed by ABCC subfamily and ABCB subfamily. The distribution of each ABC transporter on twelve chromosomes was identified. The result showed that a large number of genes were scattered around chromosome. Differentially expressed genes (DEGs) were selected for cis-acting analysis under pesticide stress. Multiple cis-elements for biological functions such as hormone-sensitive elements and defense-related elements were found to involve the initiation and regulation of transcription. Comprehensive phylogenetic analysis and domain prediction of all ABC DEGs from rice and Arabidopsis were carried out. The docking analysis of ABC transporters and pesticides provided insights into the key amino acid residues involved in the binding of the pesticides. Consequently, the results provided applicable information and reference for a more functional analysis of ABC transporter genes on regulation of pesticide metabolism and transport in plants.

Comparative genomic analysis of ABC transporter genes in Tenebrio molitor and four other tenebrionid beetles (Coleoptera: Tenebrionidea).

ATP-binding cassette (ABC) transporters, one of the largest transmembrane protein families, transport a diverse number of substate across membranes. Details of their diverse physiological functions have not been established. Here, we identified 87 ABC transporter genes in the genomes of Tenebrio molitor along with those from Asbolus verrucosus (104), Hycleus cichorii (65), and Hycleus phaleratus (80). Combining these genes (336 in total) with genes reported in Tribolium castaneum (73), we analyzed the phylogeny of ABC transporter genes in all five Tenebrionids. They are assigned into eight subfamilies (ABCA-H). In comparison to other species, the ABCC subfamily in this group of beetles appears expanded. The expression profiles of the T. molitor genes at different life stages and in various tissues were also investigated using transcriptomic analysis. Most of them display developmental specific expression patterns, suggesting to us their possible roles in development. Most of them are highly expressed in detoxification-related tissues including gut and Malpighian tubule, from which we infer their roles in insecticide resistance. We detected specific or abundant expressions of many ABC transporter genes in various tissues such as salivary gland, ovary, testis, and antenna. This new information helps generate new hypotheses on their biological significance within tissues.

Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines.

Simple SummaryCisplatin resistance is a common issue that affects patients with a variety of cancers who are treated with this drug. In this research, we present a novel epigenetic mechanism that controls the expression of ABC-family transporters, which are involved in multidrug resistance. We report that the CoREST complex may be a key factor that determines the transcription of ABC transporters in non-small cell lung and triple-negative breast cancer cells (A549 and MDA-MB-231, respectively) treated with cisplatin. By occupying gene promoters, this multi-subunit repressor prevents both an EP300-dependent increase in ABCC transcription induced by the alkylating drug and gene overexpression in cisplatin-resistant phenotypes. Moreover, the CoREST-free promoter of ABCC10 responds to cisplatin with EP300-mediated gene activation, which is only possible in p53-proficient cells.Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits—LSD1 and HDACs—restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex.

Biochemical and structural insight of regulation in yeast vacuolar ABC transporter Ycf1

Yeast Cadmium Factor-1 (Ycf1) is a vacuolar membrane localized ATP Binding Cassette (ABC) transporter belonging to the C-subfamily and plays a crucial role in cell survival during stress by maintaining the homeostasis of the heavy metals (Cd, Hg and Pb) and glutathione in cytoplasm by transporting them in vacuole. Many ABCC subfamily transporters adopts a fast switch on-and-off mechanisms to cope with stress conditions. One of such mechanism is regulation of transport activity by phosphorylation of intrinsically disordered domains, known as regulatory domains (R-domains).

The molecular evolution of function in the CFTR chloride channel.

The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand-channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.

ABCC subfamily in GtoPdb v.2021.3

Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [7, 2].

Delineating the Role of Aedes aegypti ABC Transporter Gene Family during Mosquito Development and Arboviral Infection via Transcriptome Analyses.

Aedes aegypti acts as a vector for several arboviral diseases that impose a major socio-economic burden. Moreover, the absence of a vaccine against these diseases and drug resistance in mosquitoes necessitates the development of new control strategies for vector-borne diseases. ABC transporters that play a vital role in immunity and other cellular processes in different organisms may act as non-canonical immune molecules against arboviruses, however, their role in mosquito immunity remains unexplored. This study comprehensively analyzed various genetic features of putative ABC transporters and classified them into A-H subfamilies based on their evolutionary relationships. Existing RNA-sequencing data analysis indicated higher expression of cytosolic ABC transporter genes (E & F Subfamily) throughout the mosquito development, while members of other subfamilies exhibited tissue and time-specific expression. Furthermore, comparative gene expression analysis from the microarray dataset of mosquito infected with dengue, yellow fever and West Nile viruses revealed 31 commonly expressed ABC transporters suggesting a potentially conserved transcriptomic signature of arboviral infection. Among these, only a few transporters of ABCA, ABCC and ABCF subfamily were upregulated, while most were downregulated. This indicates the possible involvement of ABC transporters in mosquito immunity.

Identification new potential multidrug resistance proteins of Saccharomyces cerevisiae

ABC (ATP-binding cassette) proteins can transport metabolic molecules and removes metabolic products and xenobiotics from the cell. The important problem is to study activity and search inhibitors of ABC proteins. There is a problem that ABC-proteins can transport hydrophobic drugs across the cell membrane due to their high substrate specificity. According to published data, Saccharomyces cerevisiae is an ideal model organism for analysis a lot of functional processes and gene activities of human cells. The aim of the present work is to reveal new potential yeast MDR proteins in S. cerevisiae with novel approach based on the cluster analysis.According to the cluster analysis of yeast ABCB subfamily, STE6 protein is turned out to be the most related to human P-gp protein. The largest number of homologues with human MDR proteins was found in the yeast ABCC subfamily. Yeast BPT1 and YCF1 proteins are shown to be the most phylogenetically close to human MRP1. In the ABCG subfamily of yeast, PDR10, PDR12, PDR15 and PDR18 are turned out to be potential proteins of multidrug resistance. The future experimental study of these subfamilies should be conducted in order to confirm the role of STE6, YCF1, BPT1, PDR10, PDR12, PDR15 and PDR18 in MDR phenotype of yeast and to study their activity modulators.

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy.

Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression. The pharmacological potential of targeting ABCC1, however, remained to be assessed. In this study, we investigated whether the blockade of ABCC1 affects prostate cancer cell proliferation using both in vitro and in vivo models. Our data demonstrate that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Collectively, these data identify ABCC1 as a novel and promising target in prostate cancer therapy.

Genome-wide characterization and expression analysis of ATP-binding cassette (ABC) transporters in strawberry reveal the role of FvABCC11 in cadmium tolerance

The ATP-binding cassette (ABC) transporter is the largest gene family and is associated with the transport of various molecules, such as heavy metal ions, secondary metabolites, and phytohormones. Strawberry is an important berry fruit and a model plant for studying fleshy fruits. However, the ABC gene family has not been identified in strawberry. In present study, 115 putative ABC genes were identified in the genome of woodland strawberry (Fragaria vesca). Based on the phylogenetic analysis results, the ABC genes were grouped into eight subfamilies (6 ABCAs, 29 ABCBs, 16 ABCCs, 1 ABCDs, 2 ABCEs, 5 ABCFs, 46 ABCGs, and 10 ABCIs). Additionally, gene structure analysis revealed that the intron-exon patterns of the ABC genes are not conserved in F. vesca. Some additional conserved motifs with group specificity were found. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis indicated ABCC subfamily gene expression across different fruit and seed developmental stages and organ profiling revealed functional diversification. Most ABCC genes exhibited preferential expression in the stems and leaves. All ABCC genes showed significant increases during the seed development stages but only ABCC8 and ABCC11 showed significant increases during fruit development. The significant changes of the 16 ABCC genes exhibited during abiotic stress treatments suggested that they might be stress-responsive genes. Over-expression of FvABCC11 in Arabidopsis partially restored seedling development under cadmium (Cd) treatment, indicated that FvABCC11 increased Cd tolerance. The results of this study provide useful information for heavy metal resistance that can be utilized to improve agricultural production.

Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics.

Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.

Germline variants in cancer therapy.

Cancer pharmacogenetics implies a complex combination of germline variants from the patient and somatic mutations in tumor cells. Somatic mutations meanwhile have become drugable targets or biomarkers, whereas germline mutations potentially predict adverse drug effects or drug response. Here, we evaluate hereditary variants in biotransforming enzymes and drug transporters, such as thiopurine S-methyltransferase, UDP-glucuronosyltransferase (UGT1A1), dihydropyrimidine dehydrogenase (DPD), as well as ABC transporters (ABCB1, ABCG2 and ABCC subfamily) with respect to cytostatics and targeted therapies. Furthermore, gene expression regulation with regards to epigenetics and posttranscriptional modification are discussed.

Functional Characterization of ABCC Proteins from Trypanosoma cruzi and Their Involvement with Thiol Transport

Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi and affects 8 million people worldwide. The main chemotherapy is based on benznidazole. The efficacy in the treatment depends on factors such as the parasite strain, which may present different sensitivity to treatment. In this context, the expression of ABC transporters has been related to chemotherapy failure. ABC transporters share a well-conserved ABC domain, responsible for ATP binding and hydrolysis, whose the energy released is coupled to transport of molecules through membranes. The most known ABC transporters are ABCB1 and ABCC1, involved in the multidrug resistance phenotype in cancer, given their participation in cellular detoxification. In T. cruzi, 27 ABC genes were identified in the genome. Nonetheless, only four ABC genes were characterized: ABCA3, involved in vesicular trafficking; ABCG1, overexpressed in strains naturally resistant to benznidazole, and P-glycoprotein 1 and 2, whose participation in drug resistance is controversial. Considering P-glycoprotein genes are related to ABCC subfamily in T. cruzi according to the demonstration using BLASTP alignment, we evaluated both ABCB1-like and ABCC-like activities in epimastigote and trypomastigote forms of the Y strain. The transport activities were evaluated by the efflux of the fluorescent dyes Rhodamine 123 and Carboxyfluorescein in a flow cytometer. Results indicated that there was no ABCB1-like activity in both T. cruzi forms. Conversely, results demonstrated ABCC-like activity in both epimastigote and trypomastigote forms of T. cruzi. This activity was inhibited by ABCC transport modulators (probenecid, indomethacin, and MK-571), by ATP-depleting agents (sodium azide and iodoacetic acid) and by the thiol-depleting agent N-ethylmaleimide. Additionally, the presence of ABCC-like activity was supported by direct inhibition of the thiol-conjugated compound efflux with indomethacin, characteristic of ABCC subfamily members. Taken together, the results provide the first description of native ABCC-like activity in T. cruzi epimastigote and trypomastigote forms, indicating that the study of the biological role for that thiol transporter is crucial to reveal new molecular mechanisms for therapeutic approaches in the Chagas disease.