Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

Taggi, Valerio; Romo, Mario Riera; Piquette-Miller, Micheline; Schwabedissen, Henriette E. Meyer zu

doi:10.3390/pharmaceutics14071376

Cited by 15 publications

(15 citation statements)

References 209 publications

(255 reference statements)

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“…Forming a filter, safety barrier as well as the site of nutrient/waste/signaling exchange, the syncytiotrophoblasts have to be well-equipped to perform these functions. Indeed, 11 members of the ABC transporter family and 9 members of the solute carrier (SLC) family have been confirmed in this tissue (Walker et al 2017 ; Taggi et al 2022 ). In a study employing quantitative targeted proteomics, ABCG2/BCRP and ABCB1/Pgp were the most abundant ABC transporters in human placental membranes with highest expression in the first trimester and decreasing by 55 and 69%, respectively, at full term (Anoshchenko et al 2020 ).…”

Section: Abc Transporters and CDmentioning

confidence: 88%

Cadmium transport by mammalian ATP-binding cassette transporters

Thévenod,

Lee

2024

Biometals

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Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body—usually in epithelia—and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.

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Section: Abc Transporters and CDmentioning

confidence: 88%

Cadmium transport by mammalian ATP-binding cassette transporters

Thévenod,

Lee

2024

Biometals

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“…Reduced P-gp expression opens the placental-glucocorticoid barrier, and a reduction in placental P-gp increases fetal exposure to glucocorticoids [ 59 ]. A recent review that discussed the actions of P-gp on the blood-placenta barrier suggests that pathological conditions during pregnancy during which the blood-placental barrier is compromised, such as preeclampsia, or following proinflammatory exposures, expression of P-gp is significantly decreased [ 60 ]. These findings together with the current data suggest that under maternal stress and alcohol exposure, the blood-placental barrier may be compromised contributing to inappropriate placental and fetal glucocorticoid regulation and exposure known to profoundly influence fetal HPA programing.…”

Section: Discussionmentioning

confidence: 99%

Independent and Combined Effects of Prenatal Alcohol Exposure and Prenatal Stress on Fetal HPA Axis Development

Bakhireva,

Solomon,

Roberts

et al. 2024

IJMS

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Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11β-HSD1, 11β-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group (p < 0.01). In multivariable modeling, PS was associated with pCRH gene expression (β = 0.006, p < 0.01), while PAE was associated with 11β-HSD2 protein expression (β = 0.56, p < 0.01). A significant alcohol-by-stress interaction was observed with respect to 11β-HSD2 protein expression (p < 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.

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“…Moreover, our PE model was associated with decreased placental expression of Pgp protein, as detected by mass spectrometry. Bcrp and Pgp are known to play critical roles in the fetal to maternal transplacental efflux of many diverse substances including many clinically important drugs and endogenous compounds (Taggi et al, 2022). Therefore, dysregulation of Bcrp and Pgp could result in increased fetal accumulation of potentially harmful substrates.…”

Section: Discussionmentioning

confidence: 99%

Use of Traditional and Proteomic Methods in the Assessment of a Preclinical Model of Preeclampsia

2023

Self Cite

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Recent studies have demonstrated downregulation of breast cancer resistance protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). BCRP is highly expressed in placenta and plays an important role in preventing xenobiotics from entering the fetal compartment. While PE is often therapeutically managed with drugs that are substrates of BCRP, there are limited studies on the impact of PE on fetal drug exposure. Due to ethical concerns, use of preclinical models is an important approach. Thus, by using proteomic and traditional methods, we characterized transporter changes in an immunological rat model of PE to determine its utility and predictive value for future drug disposition studies. PE was induced by daily administration of low-dose endotoxin (0.01-0.04 mg/kg) to rats on gestational days (GD) 13 to 16, urine was collected, and rats were sacrificed on GD17 or GD18. PE rats shared similar phenotype to PE patients, including proteinuria, and increased levels of TNF-α and IL-6.Transcript and protein levels of Bcrp were significantly downregulated in placenta of PE rats on GD18. Mdr1a, Mdr1b and Oatp2b1 mRNA were also decreased in PE. Proteomics revealed activation of various hallmarks of PE including immune activation, oxidative stress, endoplasmic reticulum stress and apoptosis. Overall, our results demonstrated that the immunological PE rat model exhibits numerous similarities to human PE along with dysregulation of placental transporters. Therefore, this model may be useful in examining the impact of PE on the maternal and fetal disposition of BCRP substrates.

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Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

Cited by 15 publications

References 209 publications

Cadmium transport by mammalian ATP-binding cassette transporters

Cadmium transport by mammalian ATP-binding cassette transporters

Independent and Combined Effects of Prenatal Alcohol Exposure and Prenatal Stress on Fetal HPA Axis Development

Use of Traditional and Proteomic Methods in the Assessment of a Preclinical Model of Preeclampsia

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