Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Intrauterine growth restriction changes the activity of hepatic drug metabolising enzymes in the maternal and fetal liver (#19)

Grace M McBride 1 2 , Jia Yin Soo 1 2 , Jack RT Darby 1 2 , Stacey L Holman 1 2 , Mitchell C Lock 1 2 , Mike Seed 3 , Mary J Berry 4 , Michael Wiese 2 , Janna L Morrison 1 2
  1. Early Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, Australia
  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
  3. Sick Kids Hospital, Toronto, Canada
  4. University of Otago, Wellington, New Zealand

Introduction: Intrauterine growth restriction (IUGR) affects 6-10% of babies worldwide[1] and is characterised by impaired growth in utero, failure to reach genetic growth potential and can result in increased risk of non-communicable diseases in adulthood. Many IUGR babies require treatment with medications; however, it has been shown that there is reduced activity of hepatic drug metabolising enzyme (DME) CYP3A4 in neonatal IUGR lambs [2]. We aimed to determine the impact of IUGR on the in vitro activity of the most common CYP450 isoenzymes, CYP3A4 and CYP2D6, in the liver of placentally restricted (PR) pregnant ewes and their fetuses [3].

Methods:  At 139d gestation, ewes carrying Control (n=12) or IUGR (n=10) fetuses were euthanised and livers collected. Microsomal protein was extracted from the maternal and fetal liver and incubated with known concentrations of probe drug (CYP2D6; Dextromethorphan and CYP3A4; Midazolam) to elicit cytochrome P450 metabolism. DME activity was determined by the quantity of metabolite produced measured using LC-MS/MS and expressed as nanomoles produced per milligram of microsomal protein per minute of incubation time (nmol/mg/min). Metabolite production was compared between Control and IUGR maternal and fetal samples using a 2-way ANOVA (age and growth) with Bonferroni’s correction for multiple comparisons.

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Results and Discussion: Fetal weight, placental weight, PaO2, and relative liver weights were significantly lower in IUGR than Control fetuses. CYP3A4 activity was increased in liver samples of PR ewes (Figure 1). CYP2D6 activity was not significantly different in IUGR fetal livers. Fetal CYP3A4 activity was below the limit of quantification in most samples (n=20), as there is limited fetal CYP3A4 activity.

Conclusion: The increased production of drug metabolites in the maternal livers of IUGR fetuses suggests increased DME activity by CYP3A4. This may be a protective mechanism of the mother to avoid excess fetal xenobiotic exposure during an IUGR pregnancy.

 

  1. Organisation for Economic Co-Operation and Development, Health at a Glance 2017: OECD indicators. 2017, OECD Publishing: Paris.
  2. Soo, J.Y., et al., Intrauterine growth restriction may reduce hepatic drug metabolism in the early neonatal period. Pharm Res, 2018.
  3. Anderson, G.D., Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol, 2006. 2(6): p. 947-60.