Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy

Kammala, Ananth Kumar; Lintao, Ryan C. V.; Vora, Natasha; Mosebarger, Angela; Khanipov, Kamil; Golovko, George; Yaklic, Jerome L.; Peltier, Morgan R.; Conrads, Thomas P.; Menon, Ramkumar

doi:10.1016/j.lfs.2022.120867

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…In previous studies, we have reported similar expression patterns of transporter proteins and cytochrome P450 enzymes in fetal membranes and placental tissues ( Ganguly et al, 2021 ; Kammala et al, 2021 ; Kammala AK. et al, 2022 ; Kammala A. et al, 2022 ).…”

Section: Discussionmentioning

confidence: 54%

“…As one of the feto-maternal interfaces (FMi) during pregnancy, the placenta is the primary organ involved in drug transportation and metabolism ( Garnica and Chan, 1996 ; Gulati and Gerk, 2009 ; Al-Enazy et al, 2017 ). However, the fetal membranes surrounding the intrauterine cavity also express transporter proteins (e.g., P-gp, BCRP-1, and OATPs) and metabolic enzymes (CYP P450 enzymes) ( Ganguly et al, 2021 ; Kammala et al, 2021 ; Kammala AK. et al, 2022 ; Kammala A. et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Microfluidic technology and simulation models in studying pharmacokinetics during pregnancy

Kammala,

Richardson,

Radnaa

et al. 2023

Front. Pharmacol.

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Introduction: Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents.Methods: We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data.Results: Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%.Discussion: The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as “therapeutic orphans” due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Microfluidic technology and simulation models in studying pharmacokinetics during pregnancy

Kammala,

Richardson,

Radnaa

et al. 2023

Front. Pharmacol.

Self Cite

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“…The results indicate that high-dose APAP treatment at 20 mM caused upregulation of CYP2E1 and CYP1A2. CYP2E1 and CYP1A2 are highly expressed in human fetal livers and involve in the biotransformation of xenobiotics [57]. These results imply that this liver model can be potentially used as a novel platform for pediatric or in-utero drug assessment studies.…”

Section: Discussionmentioning

confidence: 89%

Development of a high-throughput micropatterned agarose scaffold for consistent and reproducible hPSC-derived liver organoids

Jiang

Jin

et al. 2022

Biofabrication

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Liver organoids represent emerging human-relevant in vitro liver models that have a wide range of biomedical applications in basic medical studies and preclinical drug discovery. However, the generation of liver organoids currently relies on the conventional Matrigel dome method, which lacks precise microenvironmental control over organoid growth and results in significant heterogeneity of the formed liver organoids. Here, we demonstrate a novel high-throughput culture method to generate uniform liver organoids from human pluripotent stem cell-derived foregut stem cells in micropatterned agarose scaffold. By using this approach, more than 8000 uniformly-sized liver organoids containing liver parenchyma cells, non-parenchymal cells, and a unique stem cell niche could be efficiently and reproducibly generated in a 48-well plate with a size coefficient of variation significance smaller than that in the Matrigel dome. Additionally, the liver organoids highly expressed liver-specific markers, including ALB, HNF4α, and AFP, and displayed liver functions, such as lipid accumulation, glycogen synthesis, albumin secretion, and urea synthesis. As a proof of concept, we evaluated the acute hepatotoxicity of acetaminophen (APAP) in these organoids and observed APAP-induced liver fibrosis. Overall, we expect that the liver organoids will facilitate wide biomedical applications in hepatotoxicity analysis and liver disease modeling.

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“…The cytochrome P450 enzymatic system (CYP450) are the most important phase 1 enzymes in the placenta. The majority of CYP enzymes carry steroid-metabolizing functions (steroidogenesis); however, many CYP enzymes are also involved in xenobiotic metabolism, playing prominent roles in the elimination of pharmaceuticals and environmental chemicals. − CYP enzyme expression and activity in the placenta , and fetal membranes are lower than in the adult liver, which means that the fetus has a much lower capacity to metabolize xenobiotics compared to the mother. On the other side, sterol and steroid-related CYPs (CYP19A1, crucial for conversion of androgens to estrogens; CYP11A1, crucial for conversion of cholesterol in pregnenolone) are highly expressed in placenta and fetal liver compared to adult liver …”

Section: Placenta: a Unique Organ For Monitoring The Prenatal Periodmentioning

confidence: 99%

A Critical Review on the Opportunity to Use Placenta and Innovative Biomonitoring Methods to Characterize the Prenatal Chemical Exposome

Contini,

Béranger,

Multigner

et al. 2023

Environ. Sci. Technol.

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Adverse effects associated with chemical exposures during pregnancy include several developmental and reproductive disorders. However, considering the tens of thousands of chemicals present on the market, the effects of chemical mixtures on the developing fetus is still likely underestimated. In this critical review, we discuss the potential to apply innovative biomonitoring methods using high-resolution mass spectrometry (HRMS) on placenta to improve the monitoring of chemical exposure during pregnancy. The physiology of the placenta and its relevance as a matrix for monitoring chemical exposures and their effects on fetal health is first outlined. We then identify several key parameters that require further investigations before placenta can be used for large-scale monitoring in a robust manner. Most critical is the need for standardization of placental sampling. Placenta is a highly heterogeneous organ, and knowledge of the intraplacenta variability of chemical composition is required to ensure unbiased and robust interindividual comparisons. Other important variables include the time of collection, the sex of the fetus, and mode of delivery. Finally, we discuss the first applications of HRMS methods on the placenta to decipher the chemical exposome and describe how the use of placenta can complement biofluids collected on the mother or the fetus.

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Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy

Cited by 10 publications

References 53 publications

Microfluidic technology and simulation models in studying pharmacokinetics during pregnancy

Microfluidic technology and simulation models in studying pharmacokinetics during pregnancy

Development of a high-throughput micropatterned agarose scaffold for consistent and reproducible hPSC-derived liver organoids

A Critical Review on the Opportunity to Use Placenta and Innovative Biomonitoring Methods to Characterize the Prenatal Chemical Exposome

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