Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

Cressman, Alex; McDonald, Chloë R.; Silver, Karlee; Kain, Kevin C.; Piquette-Miller, Micheline

doi:10.1124/dmd.113.053983

Cited by 19 publications

(31 citation statements)

References 55 publications

(56 reference statements)

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“…It was observed that the placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the mice group with malaria infection as compared to the control group. In addition, the Mdr1 protein expression was also decreased in the malaria infected group compared to control (302). …”

Section: Recent Findings From Studies Involving Multiple Abc Transmentioning

confidence: 99%

“…While saquinavir is also a substrate for MRP1, despite the fact that MRP1 levels are higher at late gestation, saquinavir showed increased placental transport probably because of the basolateral localization (300). Cressman et al (302) studied the impact of malaria infection on the expression of placental ABC transporters in pregnant mice. It was observed that the placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the mice group with malaria infection as compared to the control group.…”

Section: Recent Findings From Studies Involving Multiple Abc Transmentioning

confidence: 99%

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Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

et al. 2016

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The human placenta fulfills a variety of essential functions during prenatal life. Several ABC transporters are expressed in the human placenta, where they play a role in the transport of endogenous compounds and may protect the fetus from exogenous compounds such as therapeutic agents, drugs of abuse, and other xenobiotics. To date, considerable progress has been made toward understanding ABC transporters in the placenta. Recent studies on the expression and functional activities are discussed. This review discusses the placental expression and functional roles of several members of ABC transporter subfamilies B, C, and G including MDR1/P-glycoprotein, the MRPs, and BCRP, respectively. Since placental ABC transporters modulate fetal exposure to various compounds, an understanding of their functional and regulatory mechanisms will lead to more optimal medication use when necessary in pregnancy.

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Section: Recent Findings From Studies Involving Multiple Abc Transmentioning

confidence: 99%

Section: Recent Findings From Studies Involving Multiple Abc Transmentioning

confidence: 99%

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

et al. 2016

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“…Emerging evidence has demonstrated that expression and function of drug transporters are modulated by inflammation [25–30]. Liver, intestine, kidney, blood-brain barrier and placenta are the main studied tissues and the modulation of transporter activity has been connected to the activity of proinflammatory cytokines, including IL1, IL6 and TNFα [29].…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers

et al. 2016

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Inflammation in the mammary gland (mastitis) is the most common disease in dairy herds worldwide, often caused by the pathogens Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Little is known about the effects of mastitis on drug transporters and the impact on transporter-mediated excretion of drugs into milk. We used murine mammary epithelial HC11 cells, after lactogenic differentiation into a secreting phenotype, and studied gene expressions of ABC- and SLC- transporters after treatment of cells with S. aureus and lipopolysaccharide, an endotoxin secreted by E. coli. The studied transporters were Bcrp, Mdr1, Mrp1, Oatp1a5, Octn1 and Oct1. In addition, Csn2, the gene encoding β-casein, was analyzed. As biomarkers of the inflammatory response, gene expressions of the cytokines Il6 and Tnfα and the chemokine Cxcl2 were determined. Our results show that S. aureus and LPS treatment of cells, at non-cytotoxic concentrations, induced an up-regulation of Mdr1 and of the inflammatory biomarkers, except that Tnfα was not affected by lipopolysaccharide. By simple regression analysis we could demonstrate statistically significant positive correlations between each of the transporters with each of the inflammatory biomarkers in cells treated with S. aureus. The coefficients of determination (R2) were 0.7–0.9 for all but one correlation. After treatment of cells with lipopolysaccharide, statistically significant correlations were only found between Mdr1 and the two parameters Cxcl2 and Il6. The expression of Csn2 was up-regulated in cells treated with S. aureus, indicating that the secretory function of the cells was not impaired. The strong correlation in gene expressions between transporters and inflammatory biomarkers may suggest a co-regulation and that the transporters have a role in the transport of cytokines and chemokines. Our results demonstrate that transporters in mammary cells can be affected by infection, which may have an impact on transport of essential compounds and contaminants into milk.

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“…Such changes have been observed previously during MiP; for example, malaria has been shown to alter placental expression of SLC amino acid and glucose transporters, ultimately preventing sufficient foetal access to these substrates and potentially contributing foetal growth restriction . Additionally, using the Plasmodium berghei ANKA (PbA) murine model of MiP, we previously observed a downregulation in the expression of the ABC drug transporters Mdr1a, Mdr1b, Mrp1‐3 and Bcrp in the placenta of malaria‐infected animals . Furthermore, ABC and SLC transporters located in other tissues such as the liver and kidney play an important role in the absorption, distribution and elimination of drugs.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of solute carrier transporters in malaria‐infected pregnant mice

Najjar

McColl

Weckman

et al. 2019

Parasite Immunology

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Summary Aims Malaria in pregnancy (MiP) alters the expression of ATP‐binding cassette efflux transporters in maternal and foetal tissues, as well as the placenta. Malaria induces oxidative stress, and pregnancy is associated with arginine deficiency. We hypothesized that reducing oxidative stress during MiP by supplementation with L‐arginine, a NO precursor, would attenuate transcriptional changes in a second superfamily of transporters, solute carrier (SLC) transporters, and improve pregnancy outcomes. Methods and Results Pregnant BALB/c mice receiving L‐arginine (1.2%) in water, or water alone, were infected with Plasmodium berghei ANKA on gestational day 13 and sacrificed on gestational day 19. Compared to controls, the mRNA of numerous SLC transporters was downregulated in maternal and foetal tissues, as well as in the placentas of infected mice. While supplementation with L‐arginine did improve foetal viability, it did not improve the mRNA expression of oxidative stress markers, transporters nor other indices of foetal and maternal health. Moreover, amino acid uptake transporters were downregulated upon infection, which could potentially contribute to decreased foetal birthweight. Conclusions Malaria in pregnancy significantly alters the expression of SLC transporters in maternal and foetal tissues as well as the placenta, regardless of L‐arginine supplementation. Further studies to investigate methods of reducing oxidative stress in MiP are warranted.

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Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

Cited by 19 publications

References 55 publications

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers

Dysregulation of solute carrier transporters in malaria‐infected pregnant mice

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