The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field

Blanco-Castañeda, Ricardo; Galavíz-Hernández, Carlos; Souto, Paula C. S.; Lima, Victor Vitorino; Giachini, Fernanda R.; Escudero, Carlos; Damiano, Alicia E.; Barragán-Zúñiga, L. Jazel; Martínez‐Aguilar, Gerardo; Sosa-Macías, Martha

doi:10.1080/17512433.2020.1733412

Cited by 18 publications

(11 citation statements)

References 191 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transporters and membrane markers that were successfully quantified are shown in green (basal membrane proteins) and blue (apical membrane proteins) (success criterion: LLOQ 5-fold signal-to-noise ratio), whereas the ones targeted but not quantifiable (below LLOQ) are shown in gray. Most abundant drug-metabolizing enzymes that are present in the placenta but upon which no attempt to quantify was made are indicated in the red oval ( Blanco-Castañeda et al, 2020 ). The key studies informing membrane localization of the transporters were: P-gp ( Atkinson et al, 2006 ; Sun et al, 2006 ); BCRP ( Maliepaard et al, 2001 ); SERT ( Balkovetz et al, 1989 ; Bottalico et al, 2004 ); NET( Bottalico et al, 2004 ); OCT3 ( Lee et al, 2018 ); OAT4 ( Ugele et al, 2008 ) and OATP2B1 ( Ugele et al, 2008 ); and key review articles ( Myllynen et al, 2009 ; Vahakangas and Myllynen, 2009 ; Joshi et al, 2016 ; Han et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

et al. 2020

View full text Add to dashboard Cite

Some women take medication during pregnancy to address a variety of clinical conditions. Because of ethical and logistical concerns, it is impossible to determine fetal drug exposure, and therefore fetal risk, during pregnancy. Hence, alternative approaches need to be developed to predict maternal-fetal drug exposure throughout pregnancy. To do so, we previously developed and verified a maternalfetal physiologically based pharmacokinetic model, which can predict fetal exposure to drugs that passively cross the placenta. However, many drugs are actively transported by the placenta (e.g., human immunodeficiency virus protease inhibitors). To extend our maternal-fetal physiologically based pharmacokinetic model to these actively transported drugs, we determined the gestational age-dependent changes in the protein abundance of placental transporters. Total cellular membrane fractions from first trimester (T1; n = 15), second trimester (T2; n = 19), and term (n = 15) human placentae obtained from uncomplicated pregnancies were isolated by ultracentrifugation. Transporter protein abundance was determined by targeted quantitative proteomics using liquid chromatography tandem mass specrometry. We observed that breast cancer resistance protein and P-glycoprotein abundance significantly decreased from T1 to term by 55% and 69%, respectively (per gram of tissue). Organic anion-transporting polypeptide (OATP) 2B1 abundance significantly decreased from T1 to T2 by 32%. In contrast, organic cation transporter (OCT) 3 and organic anion transporter 4 abundance significantly increased with gestational age (2-fold from T1 to term, 1.6-fold from T2 to term). Serotonin transporter and norepinephrine transporter did not change with gestational age. The abundance of bile salt export pump, multidrug resistance-associated protein 1-5, Na +-taurocholate cotransporting polypeptide, OATP1B1, OATP1B3, OCTN1-2, concentrative nucleoside transporter 1-3, equilibrative nucleoside transporter 2, and multidrug and toxin extrusion 1 could not be quantified. These data can be incorporated into our maternal-fetal physiologically based pharmacokinetic model to predict fetal exposure to drugs that are actively transported across the placenta. SIGNIFICANCE STATEMENT We quantified the protein abundance of key placental uptake and efflux transporters [organic cation transporter (OCT) 3, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)] across gestational ages (first trimester, second trimester, and term) using quantitative targeted proteomics. We observed that the protein abundance of P-gp and BCRP decreased, whereas that of OCT3 increased with gestational age. Incorporating the protein abundance determined in this study into maternal-fetal physiologically based pharmacokinetic model can help us better predict fetal drug exposure to substrates of these transporters.

show abstract

Section: Introductionmentioning

confidence: 99%

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As human UGT isoenzymes are only expressed several months after birth ( Strassburg et al, 2002 ) conjugation of parabens in the fetus has been suggested to occur, most likely to a lesser extent, predominantly by SULTs which are expressed in the human liver of all age groups including fetuses ( Hines, 2008 ). Little is known about the metabolic fate of parabens in the human placenta, but several studies have reported higher SULT, and lower UGT activity in the human placenta compared with the liver ( Blanco-Castañeda et al, 2020 , Coughtrie et al, 1988 ). The proportion of free paraben in the body is therefore also dependent on the efficiency of the paraben metabolizing enzymes, but little is known about the fetal exposure profile of parabens ( Scientific Committee on Consumer Safety (SCCS) 2011 ).…”

Section: Discussionmentioning

confidence: 99%

In utero exposure to parabens and early childhood BMI z-scores – Associations between placental ethyl paraben, longitudinal BMI trajectories and cord blood metabolic biomarkers

Reimann

Vrijens

Roels

et al. 2021

Environment International

View full text Add to dashboard Cite

show abstract

“…Hopefully, the placenta and, in particular, STB counts with a range of enzymes involved not only in the synthesis of different hormones or metabolic reactions but also in detoxification and efflux of xenobiotics, acting in a similar manner to the hepatocytes in the adult [69]. These enzymes are known as xenobiotic-metabolizing enzymes (XMEs), participating in the biotransformation and elimination of maternal and fetal hormones, dietary compounds, drugs, and environmental chemicals [70]. Among these enzymes, of note is the role of cytochrome P450 (CYP), also found in hepatic cells.…”

Section: Placental Barriermentioning

confidence: 99%

The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease

Ortega

Fraile-Martínez

García-Montero

et al. 2022

Cells

View full text Add to dashboard Cite

The placenta is a central structure in pregnancy and has pleiotropic functions. This organ grows incredibly rapidly during this period, acting as a mastermind behind different fetal and maternal processes. The relevance of the placenta extends far beyond the pregnancy, being crucial for fetal programming before birth. Having integrative knowledge of this maternofetal structure helps significantly in understanding the development of pregnancy either in a proper or pathophysiological context. Thus, the aim of this review is to summarize the main features of the placenta, with a special focus on its early development, cytoarchitecture, immunology, and functions in non-pathological conditions. In contraposition, the role of the placenta is examined in preeclampsia, a worrisome hypertensive disorder of pregnancy, in order to describe the pathophysiological implications of the placenta in this disease. Likewise, dysfunction of the placenta in fetal growth restriction, a major consequence of preeclampsia, is also discussed, emphasizing the potential clinical strategies derived. Finally, the emerging role of the placenta in maternal chronic venous disease either as a causative agent or as a consequence of the disease is equally treated.

show abstract

The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field

Cited by 18 publications

References 191 publications

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

In utero exposure to parabens and early childhood BMI z-scores – Associations between placental ethyl paraben, longitudinal BMI trajectories and cord blood metabolic biomarkers

The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease

Contact Info

Product

Resources

About