Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

Joshi, Anand; Vaidya, Soniya; St‐Pierre, Marie V.; Mikheev, Andrei M.; Desino, Kelly E.; Nyandege, Abner; Audus, Kenneth L.; Unadkat, Jashvant D.; Gerk, Phillip M.

doi:10.1007/s11095-016-2028-8

Cited by 91 publications

(91 citation statements)

References 292 publications

(416 reference statements)

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“…As these efflux transporters are expressed at the apical side of the syncytiotrophoblast layer, they possibly play a role in reducing foetal exposure. Xenobiotics interacting with these transporters may also influence placental transfer of DAAs . Since placental transporter expression changes during pregnancy, placental transfer may be also dependent on timing of treatment during pregnancy.…”

Section: Placental Handling Of Direct‐acting Antiviralsmentioning

confidence: 99%

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

Freriksen

Seyen²,

Judd

et al. 2019

Aliment Pharmacol Ther

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Summary Background With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct‐acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended. Aim To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation Methods A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation. Results Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy‐induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester. Conclusions Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination.

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Section: Placental Handling Of Direct‐acting Antiviralsmentioning

confidence: 99%

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

Freriksen

Seyen²,

Judd

et al. 2019

Aliment Pharmacol Ther

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“…The 1 mL DEX-SS-IND/DOX micelle solution was transferred into a dialysis membrane (MWCO 7.0 kDa) and then immersed in 20 mL incubation media with constant shaking at 70 rpm at 37°C. At predetermined time intervals (1,2,4,6,8,10,12,24,36, and 48 hours), the samples were collected and replaced with fresh medium. DOX content was measured using fluorescence spectrophotometry.…”

Section: Synthesis and Characterization Of Dex-ss-indmentioning

confidence: 99%

“…3 The most commonly reported efflux membrane transporter MDR-associated proteins (MRPs) are extensively overexpressed in various tumor cells and actively pump the broad spectrum of chemotherapeutics outward from the cells. 4,5 Several chemotherapeutics can be served as substrates for MRPs. 6,7 The antitumor agent doxorubicin (DOX) is widely used for the treatment of various solid tumors via interacting with DNA through intercalation and inhibiting topoisomerase II, but it is also a substrate for MRPs.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

Zhou¹,

Wang²,

Ying³

et al. 2017

IJN

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Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.

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“…ABC transporters regulate the flux of xenobiotics across cell membranes. ABCC1, ABCB1 and ABCG2 are all expressed in both BBB (92) and placenta (93,94), which suggests they may exert a protective role for the fetus, and their substrates include glutathione conjugates and hydrophobic compounds (92). CFTR, also an ABC transporter, was the second gene with the highest load of relevant SNVs.…”

Section: Interactions Between Detoxification and Barrier Genes Targetmentioning

confidence: 99%

A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

Santos

Rasga

Marques

et al. 2019

Preprint

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Introduction: Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder defined by deficits in social communication and interaction and repetitive and stereotyped interests and behaviors. ASD heritability estimates of 50-83% support a strong role of genetics in its onset, with large sequencing studies reporting a high burden of rare potentially pathogenic copy number variants (CNVs) and single nucleotide variants (SNVs) in affected subjects. Recent data strongly suggests that prenatal to postnatal exposure to ubiquitous environmental factors (e.g. environmental toxins, medications and nutritional factors) contribute to ASD risk. Detoxification processes and physiological permeability barriers (i.e. blood-brain barrier, placenta and respiratory cilia) are crucial in regulating exposure and response to external agents during early development. Thus, the objectives of this study were: 1) to find genes involved in detoxification and regulation of barriers permeability with a high load of relevant CNVs and SNVs in ASD subjects; 2) to explore interactions between the identified genes and environmental factors relevant for the disorder. Material and Methods: Through literature and databases review we searched for genes involved in detoxification and regulation of barriers permeability processes. Genetic data collected from large datasets of subjects with ASD (Autism Genome Project (AGP), Simmons Simplex Collection (SSC), and Autism Sequencing Consortium (ASC)) was used to identify potentially pathogenic variants targeting detoxification and barrier genes. Data from control subjects without neuropsychiatric disorder history was used for comparison purposes. The Comparative Toxicogenomics Database (CTD) was interrogated to identify putatively relevant gene-environment interactions reported in humans throughout the literature. Results:We compiled a list of 519 genes involved in detoxification and regulation of permeability barriers. The analysis of AGP and SSC data resulted in the identification of 7 genes more-frequently targeted by CNVs in ASD subjects from both datasets, after Bonferroni correction for multiple testing (AGP: P<3.5211x10 -4 ; SSC: P< 4.587x10 -4 ). Moreover, 8 genes were exclusively targeted by CNVs from ASD subjects. Regarding SNVs analyses using the ASC dataset, we found 40 genes targeted by potentially pathogenic loss-of-function and/or missense SNVs exclusive to 6 or more cases. The CTD was interrogated for interactions between 55 identified genes and 54 terms for unique chemicals associated with the disorder. A total of 212 gene-environment interaction pairs, between 51/55 (92.7%) genes and 38/54 (70.4%) chemicals, putatively relevant for ASD, were discovered. ABCB1, ABCG2, CYP2C19, GSTM1, CYP2D6, and SLC3A2 were the genes that interacted with more chemicals, while valproic acid, benzo(a)pyrene (b(a)p), bisphenol A, particulate matter and perfluorooctane sulfonic acid (PFOS) were the top chemicals. Discussion: The identified genes code for functionally diverse proteins...

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Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

Cited by 91 publications

References 292 publications

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

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