Maternal MitoQ Treatment Is Protective Against Programmed Alterations in CYP Activity Due to Antenatal Dexamethasone

Background/Objectives: In pregnancy threatened by preterm birth, antenatal corticosteroids (ACS) are administered to accelerate fetal lung maturation. However, they have side effects, including the production of reactive oxygen species that can impact cytochrome P450 (CYP) activity. We hypothesised that antioxidants could protect a fetus treated with ACS during gestation and prevent the programming of altered hepatic CYP activity in the offspring. The primary outcome of our study was the impact of different maternal treatments on the activity of hepatic drug-metabolising enzymes in offspring. Methods: At 100 ± 1 days gestational age (dGA, term = 147 dGA), 73 ewes were randomly allocated to the following: saline (5 mL IV daily 105-137 ± 2 dGA, n = 17), ACS (Dexamethasone (Dex); 12 mg IM at 115 and 116 dGA; n = 25), MitoQ (6 mg/kg MS010 IV, daily bolus 105-137 ± 2 dGA; n = 17) or Dex and MitoQ (Dex+MitoQ; n = 14). CYP activity and protein abundance were assessed using functional assays and Western blot. Results: Dex decreased the hepatic activity of fetal CYP3A (-56%, P_Dex = 0.0322), and 9 mo lamb CYP1A2 (-22%, P_Dex = 0.0003), CYP2B6 (-36%, P_Dex = 0.0234), CYP2C8 (-34%, P_Dex = 0.0493) and CYP2E1 (-57%, P_Dex = 0.0009). For all, except CYP1A2, activity returned to control levels with Dex+MitoQ in 9 mo lambs. In 9 mo lambs, MitoQ alone increased activity of CYP2B6 (+16%, P_MitoQ = 0.0011) and CYP3A (midazolam, +25%, P_MitoQ = 0.0162) and increased CAT expression (P_MitoQ = 0.0171). Dex+MitoQ increased CYP3A4/5 activity (testosterone, +65%, P_Intx < 0.0003), decreased CYP1A2 activity (-14%, P_Intx = 0.0036) and decreased mitochondrial abundance (P_Intx = 0.0051). All treatments decreased fetal hepatic DRP1, a regulator of mitochondrial fission (P_Dex = 0.0055, P_MitoQ = 0.0006 and P_Intx = 0.0034). Conclusions: Antenatal Dex reduced activity of only one CYP in the fetus but programmed the reduced activity of several hepatic CYPs in young adult offspring, and this effect was ameliorated by combination with MitoQ.