Activities of metabolizing enzymes in human placenta

Mohammed, Ali Mustafa; Huuskonen, Pasi; Juvonen, Risto O.; Sahlman, Heidi; Repo, Jenni; Myöhänen, Kirsi; Myllynen, Päivi; Woo, Chit-Shing Jackson; Karttunen, Vesa; Vähäkangas, Kirsi

doi:10.1016/j.toxlet.2020.02.014

Cited by 8 publications

(6 citation statements)

References 46 publications

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Section: Resultsmentioning

confidence: 99%

“…Fetus exposure to drugs and chemicals also depends on maternal pharmacokinetics, such as the volume of distribution, the rate of placental metabolism and excretion, and the hemodynamic changes induced in the mother during pregnancy [ 114 , 115 ]. For instance, although mycotoxin T-2 is actively transported, its metabolite HT-2 depends on passive diffusion [ 114 , 115 ]. During pregnancy, the volume of distribution, renal plasma flow, and glomerular filtration rate are increased, leading to lower drug concentration and elevated renal clearance of xenobiotics [ 116 , 117 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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Background: The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. Methods: A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. Results: During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Conclusions: Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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Section: Introductionmentioning

confidence: 99%

“…Studies conducted on animals revealed that CsA had an advert effect on the reproductive system [6,7]. As far as the concentration of the metabolites of CsA was concerned, their high values were observed in the placenta [6], which indicated that this tissue contains enzyme-metabolizing CsA [7]. Classification of this ID performed by the FDA indicates that the risk for humans' health cannot be ruled out, when CsA is used during pregnancy (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Exposition to Different Immunosuppressive Protocols Results in Vacuolar Degeneration of Hepatocytes

Wilk

Szypulska-Koziarska

Oszutowska–Mazurek

et al. 2023

Biology

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Immunosuppressive drugs are essential for transplant recipients, since they prolong proper function of graft; however, they affect the morphology and function of organs, including liver. One commonly observed alteration in hepatocytes is vacuolar degeneration. Numerous medications are contraindicated in pregnancy and breastfeeding, mostly due to a lack of data concerning their advert effects. The aim of the current study was to compare the effects of prenatal exposition to different protocols of immunosuppressants on vacuolar degeneration in the hepatocytes of livers of rats. Thirty-two livers of rats with usage of digital analysis of the images were examined. Area, perimeter, axis length, eccentricity and circularity regarding vacuolar degeneration were analysed. The most prominent vacuolar degeneration in hepatocytes in the aspects of presence, area and perimeter was observed in rats exposed to tacrolimus, mycophenolate mofetil and glucocorticoids, and cyclosporine A, everolimus with glucocorticoids.This is the first study that demonstrates the results of the influence of multidrug immnunosuppression distributed in utero on the hepatic tissue of offspring.

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“…Ethanol is metabolized in the liver to acetaldehyde via oxidative pathways: 90% approximately by ethanol dehydrogenase (ADH) and 10% by cytochrome P450 2E1 (CYP2E1), an isoform of the cytochrome P450 system (CYP) [ 5 ]; then, acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH) and enters the Krebs cycle to produce water and carbon dioxide (CO 2 ). Additionally, catalase (CAT) can metabolize ethanol in the presence of a hydrogen peroxide (H 2 O 2 )-generating system, such as the enzyme complex NADPH oxidase or the enzyme xanthine oxidase [ 6 ]. As a result of ethanol metabolism by CYP2E1, localized in the junctional zone of the placenta [ 7 ], reactive oxygen species (ROS) are produced, triggering DNA damage and promoting the oxidation of lipids, proteins, and other metabolites [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System

Martín-Estal

Fajardo-Ramírez

León

et al. 2022

Biology

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Ethanol use during pregnancy is a risk factor for developing adverse outcomes. Its metabolism by cytochrome P450 2E1 (CYP2E1) produces radical oxygen species (ROS), promoting cellular injury and apoptosis. To date, no studies have been conducted to elucidate the teratogenic effects due to both IGF-1 deficiency and ethanol consumption in mice placentas. The aim of this study is to determine the effect of ethanol consumption on the placenta and liver of partially IGF-1-deficient mice, the role of metabolism via CYP2E1, and the antioxidant enzyme system. Heterozygous (HZ, Igf1+/−) pregnant female mice were given water or 10% ethanol. Wild-type (WT, Igf1+/+) female mice were used as controls. At gestational day 19, pregnant dams were euthanized, and maternal liver and placentas were collected. Pregnant HZ dams were smaller than controls, and this effect was higher due to ethanol consumption. Cyp2e1 gene was overexpressed in the liver of HZ pregnant dams exposed to ethanol; at the protein level, CYP2E1 is reduced in placentas from all genotypes. The antioxidant enzymatic system was altered by ethanol consumption in both the maternal liver and placenta. The results in this work hint that IGF-1 is involved in intrauterine development because its deficiency exacerbates ethanol’s effects on both metabolism and the placenta.

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Activities of metabolizing enzymes in human placenta

Cited by 8 publications

References 46 publications

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Prenatal Exposition to Different Immunosuppressive Protocols Results in Vacuolar Degeneration of Hepatocytes

Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System

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