PMID- 35367241
OWN - NLM
STAT- MEDLINE
DCOM- 20220419
LR  - 20220419
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 298
DP  - 2022 Jun 1
TI  - Maternal-placental-fetal drug metabolism is altered by late gestation 
      undernutrition in the pregnant ewe.
PG  - 120521
LID - S0024-3205(22)00221-1 [pii]
LID - 10.1016/j.lfs.2022.120521 [doi]
AB  - 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.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Meakin, Ashley S
AU  - Meakin AS
AD  - Early Origins of Adult Health Research Group, Health and Biomedical Innovation, 
      UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, 
      South Australia, Australia.
FAU - Darby, Jack R T
AU  - Darby JRT
AD  - Early Origins of Adult Health Research Group, Health and Biomedical Innovation, 
      UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, 
      South Australia, Australia.
FAU - Holman, Stacey L
AU  - Holman SL
AD  - Early Origins of Adult Health Research Group, Health and Biomedical Innovation, 
      UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, 
      South Australia, Australia.
FAU - Wiese, Michael D
AU  - Wiese MD
AD  - Centre for Pharmaceutical Innovation, UniSA: Clinical and Health Sciences, 
      University of South Australia, Adelaide, South Australia, Australia. Electronic 
      address: michael.wiese@unisa.edu.au.
FAU - Morrison, Janna L
AU  - Morrison JL
AD  - Early Origins of Adult Health Research Group, Health and Biomedical Innovation, 
      UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, 
      South Australia, Australia. Electronic address: janna.morrison@unisa.edu.au.
LA  - eng
PT  - Journal Article
DEP - 20220331
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Chromatography, Liquid
MH  - Cytochrome P-450 CYP1A2/metabolism
MH  - Cytochrome P-450 CYP2D6/metabolism
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Female
MH  - Fetus/metabolism
MH  - Glucose/metabolism
MH  - *Hypoglycemia/metabolism
MH  - *Malnutrition/metabolism
MH  - Maternal-Fetal Exchange
MH  - Placenta/metabolism
MH  - Pregnancy
MH  - Sheep
MH  - Tandem Mass Spectrometry
OTO - NOTNLM
OT  - Cytochrome P450
OT  - Drug metabolism
OT  - Fetal development
OT  - Maternal undernutrition
OT  - Microsomes
EDAT- 2022/04/04 06:00
MHDA- 2022/04/20 06:00
CRDT- 2022/04/03 20:24
PHST- 2022/02/03 00:00 [received]
PHST- 2022/03/24 00:00 [revised]
PHST- 2022/03/27 00:00 [accepted]
PHST- 2022/04/04 06:00 [pubmed]
PHST- 2022/04/20 06:00 [medline]
PHST- 2022/04/03 20:24 [entrez]
AID - S0024-3205(22)00221-1 [pii]
AID - 10.1016/j.lfs.2022.120521 [doi]
PST - ppublish
SO  - Life Sci. 2022 Jun 1;298:120521. doi: 10.1016/j.lfs.2022.120521. Epub 2022 Mar 
      31.