Background: Alterations to the intrauterine environment, such as those brought on by maternal undernutrition, can disrupt fetal growth and development and consequently perturb certain physiological processes within the feto-placental unit, including feto-placental metabolism. It is not known how perturbations such as hypoglycemia alters the capacity to appropriately metabolise exogenous chemicals including drugs and other xenobiotics, which are taken in most pregnancies. Drug metabolism is mediated by cytochrome P450 (CYP) drug metabolising enzymes in the . Hypoglycemia reduces activity of CYP isoenzymes, reducing efficacy and safety of certain pharmaceutical therapies. We therefore hypothesised that in a sheep model of late gestation undernutrition (LGUN) feto-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 + glucose infusion via fetal femoral vein; n=6) and maintained on the diet until post-mortem. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation. Placental and hepatic microsomes were incubated with specific CYP probes and the concentration of metabolite produced was measured using Liquid Chromatography – tandem mass spectrometry (LC-MS/MS).
Results: CYP3A was not detectable in either placenta or fetal liver, and CYP1A2 was not detectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were not affected by LGUN or LGUN+G. CYP2D6 activity was significantly higher in the liver than placenta, irrespective of study group.
Conclusions: The physiological response to LGUN does not affect placental- or hepatic-specific activity of certain CYPs. Our study is the first to report functional activity of CYP1A2 and CYP2D6 in the sheep placenta and provides an experimental workflow to examine the activity of other CYP isoenzymes in the feto-placental unit.