Adverse placental effects of valproic acid: Studies in perfused human placentas

Rubinchik‐Stern, Miriam; Shmuel, Miriam; Bar, Jacob; Kovo, Michal; Eyal, Sara

doi:10.1111/epi.14078

Cited by 35 publications

(59 citation statements)

References 52 publications

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“…In our previous study in term human placentas, two folate carriers, SLC46A1 (PCFT) and FRα, were coregulated . However, in that study, whereas the expression of PCFT and FRα was mostly down‐regulated by valproate, that of RFC increased.…”

Section: Discussionmentioning

confidence: 68%

“…We previously demonstrated that when term human placentas are exposed to valproate, their carrier expression profile changes. 5 The current study suggests that valproate may already target the human placenta in early pregnancy, during organogenesis.…”

Section: Discussionmentioning

confidence: 70%

“…Initial experiments involving 3‐hour exposure to valproate demonstrated minimal changes in the mRNA levels of selected carriers (in contrast to perfused human placentas), possibly due to slow valproate uptake into placental explants in the absence of perfusion. Hence, we extended the duration of incubation to 5 days, after which several observations could be made.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we suggested that valproate might adversely affect fetal development by altering the expression of placental carriers . However, term placentas might not reveal drug effects that occur during early pregnancy, when organogenesis takes place, and the duration of perfusion studies is limited to several hours .…”

Section: Introductionmentioning

confidence: 99%

“…3 Recently, we suggested that valproate might adversely affect fetal development by altering the expression of placental carriers. [4][5][6] However, term placentas might not reveal drug effects that occur during early pregnancy, when organogenesis takes place, and the duration of perfusion studies is limited to several hours. 7 Therefore, we conducted this pilot study to evaluate the effects of subchronic exposure to valproate on villous explants from early gestation placentas.…”

Section: Introductionmentioning

confidence: 99%

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The effects of valproic acid on early pregnancy human placentas: Pilot ex vivo analysis in cultured placental villi

et al. 2019

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Summary Valproic acid is an established structural and neurodevelopmental teratogen. Recently, we demonstrated that valproate alters the barrier function of perfused term human placentas. Here, we conducted a pilot study to evaluate the effects of subchronic valproate exposure on carrier expression in cultured placental villous explants from early human pregnancies. Placental tissue of gestational age 6‐13 weeks was collected from elective pregnancy terminations in women without known epilepsy. The effects of valproate (42, 83, or 166 μg/mL) on the mRNA expression of 37 major placental carriers and related genes were evaluated by a customized gene expression array (n = 5, 5 days). Five‐day exposure to valproate was associated with high variability in gene expression. However, two main gene clusters were identified, including a cluster of three major folate carriers. Exposure to low therapeutic levels of valproate (42 μg/mL) was associated with a tendency toward reduced mRNA expression of genes encoding folate and amino acid and fatty acid carriers (P = 0.065, paired analysis). Our initial findings suggest that valproate can affect the function of the human placenta during early pregnancy.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of valproic acid on early pregnancy human placentas: Pilot ex vivo analysis in cultured placental villi

et al. 2019

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Transporters in Drug Development: International Transporter Consortium Update on Emerging Transporters of Clinical Importance

Zamek‐Gliszczynski

Sangha

Shen

et al. 2022

Clin Pharma and Therapeutics

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During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug development. Previously highlighted and new transporters were considered based on up‐to‐date clinical evidence of their importance in drug–drug interactions and potential for altered drug efficacy and safety, including drug–nutrient interactions leading to nutrient deficiencies. For the first time, folate transport pathways (PCFT, RFC, and FRα) were examined in‐depth as a potential mechanism of drug‐induced folate deficiency and related toxicities (e.g., neural tube defects and megaloblastic anemia). However, routine toxicology studies conducted in support of drug development appear sufficient to flag such folate deficiency toxicities, whereas prospective prediction from in vitro folate metabolism and transport inhibition is not well enough established to inform drug development. Previous suggestion of a retrospective study of intestinal OATP2B1 inhibition to explain unexpected decreases in drug exposure were updated. Furthermore, when the absorption of a new molecular entity is more rapid and extensive than can be explained by passive permeability, evaluation of the OATP2B1 transport may be considered. Emerging research on hepatic and renal OAT2 is summarized, but current understanding of the importance of OAT2 was deemed insufficient to justify specific consideration for drug development. Hepatic, renal, and intestinal MRPs (MRP2, MRP3, and MRP4) were revisited. MRPs may be considered when they are suspected to be the major determinant of drug disposition (e.g., direct glucuronide conjugates); MRP2 inhibition as a mechanistic explanation for drug‐induced hyperbilirubinemia remains justified. There were no major changes in recommendations from previous ITC whitepapers.

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Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

et al. 2018

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SummaryInhibition of histone deacetylases (HDACs) and subsequent hyperacetylation of histone proteins lead to altered gene expression associated with therapeutic drug effects, but also with teratogenicity. The only US Food and Drug Administration (FDA)–approved antiepileptic drug that has been consistently shown to induce histone hyperacetylation is valproic acid. More recently, lacosamide was reported to interfere with histone modifications, but histone hyperacetylation was not demonstrated. In the current study we evaluated the effects of lacosamide on histone acetylation in vitro. MDA‐MB‐231 (triple‐negative breast cancer) cells and human placental BeWo cells were exposed for 16 hours to 5‐20 μg/ml (20‐80 μm) lacosamide. Histone acetylation was evaluated by western blot analysis. We additionally measured HDAC1 activity in the presence of lacosamide. At 5, 10, and 20 μg/ml, lacosamide enhanced histone acetylation in BeWo cells by 1.7‐fold (p > 0.05), 3.4‐fold (p < 0.05), and 3.0‐fold (p > 0.05), respectively. Histone H3 acetylation and total histones H3 and H4 levels were not significantly modified (p > 0.05). The magnitude of change in histone acetylation in MDA‐MB‐231 cells was smaller (p > 0.05). In contrast to valproic acid, lacosamide did not inhibit HDAC1. Our findings suggest that the effects of lacosamide on gene expression, and the related potential antitumor activity and teratogenicity, may differ from those of valproic acid.

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Adverse placental effects of valproic acid: Studies in perfused human placentas

Abstract: Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes.

Cited by 35 publications

References 52 publications

The effects of valproic acid on early pregnancy human placentas: Pilot ex vivo analysis in cultured placental villi

The effects of valproic acid on early pregnancy human placentas: Pilot ex vivo analysis in cultured placental villi

Transporters in Drug Development: International Transporter Consortium Update on Emerging Transporters of Clinical Importance

Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

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