Maternal-placental-fetal drug metabolism is altered by late gestation undernutrition in the pregnant ewe
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Date
2022
Authors
Meakin, A.S.
Darby, J.R.T.
Holman, S.L.
Wiese, M.D.
Morrison, J.L.
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Journal article
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Life Sciences, 2022; 298(article no. 120521):1-9
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Background: Maternal undernutrition during pregnancy disrupts both fetal growth and development with perturbations to certain physiological processes within the maternal-fetal-placental unit, including metabolic function. However, it is unknown if hypoglycemia during pregnancy alters maternal-fetal-placental drug metabolism as mediated by cytochrome P450 (CYP) enzymes. Despite this, hypoglycemia reduces CYP enzyme activity in non-pregnant animals. We therefore hypothesised that in a sheep model of hypoglycemia induced by late gestation undernutrition (LGUN), maternal-fetal-placental CYP activity would be reduced, and that fetal glucose infusion (LGUN+G) would rescue reduced CYP activity.
Methods: At 115d gestation (term, 150d), ewes were allocated to control (100% metabolic energy requirement (MER); n = 11), LGUN (50% MER; n = 7) or LGUN+G (50% MER + fetal glucose infusion; n = 6) and maintained on their diets until post-mortem. Maternal-fetal-placental CYP activity assays were performed at 131-133d gestation. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation and incubated with CYP-specific probe drugs. Metabolite concentrations were measured using Liquid Chromatography – tandem mass spectrometry (LC-MS/MS).
Results: CYP2C19 and CYP3A were undetectable in placenta or fetal liver, and CYP1A2 was undetectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were unaffected by LGUN. Maternal-fetal-placental CYP1A2 activity was reduced in response to LGUN in the maternal compartment only.
Conclusions: Reduced maternal-fetal-placental CYP1A2 activity, but not placental-specific CYP1A2 activity, may lead to the developing fetus being exposed to increased concentrations of CYP1A2-specific substrates and suggests further consideration of drug dosing is required in instances of late gestation maternal undernutrition.
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Data source: Supplementary data, t https://doi.org/10.1016/j.lfs.2022.120521
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Copyright 2022 Elsevier
Access Condition Notes: Accepted manuscript available after 1 April 2023