Long‐term Hypoxia Alters Cytochrome P450 Activity During Pregnancy in Ovine Species

Abstract

The absolute avoidance of medication during pregnancy, though desired, might not be practical because of preexisting co‐morbidities, pregnancy induced disorders (e.g. gestational diabetes), preeclampsia, or even fetal disorders. When indicated, the use of medication could be a major source of stress and apprehension for the pregnant woman and her care‐provider. The inadequacy of data on drug safety during pregnancy is one contributory factor to this apprehension. Compounding this problem is the resurgence of the use of illicit drugs and abuse of prescription medications such as opioids during pregnancy. It is well‐established that drug metabolism is altered during pregnancy. Changes in maternal drug metabolism can also occur during pathologic conditions associated with exposure to varying levels of hypoxia.Cytochrome P450 (CYP) 3A accounts for the metabolism of over 60% of clinically used drugs and environmental xenobiotics. CYP expression is altered by pregnancy as well as pathologies attributable to hypoxia like eclampsia, placental insufficiency and illicit drug use. We hypothesize here that long term hypoxia (LTH) alters CYP activity in pregnant ovine species via epigenetic mechanisms. To generate the hypoxic experimental groups, non‐pregnant and pregnant sheep were taken to an altitude of 3280m above sea level for 110 days while normoxic controls for each group were kept at sea level. Post sacrifice, precise cuts of liver segments were cleaned of blood and assayed for CYP3A4 activity and total methylated cytosines. Compared to their normoxic controls, LTH increased hepatic CYP3A4 catalytic activity in non‐pregnant sheep (118%) and pregnant sheep (142%). Whereas hepatic CYP3A4 catalytic activity was not significantly different between non‐pregnant and pregnant normoxic sheep, it was decreased in pregnant hypoxic sheep (20%) compared to non‐pregnant hypoxic sheep. Western blot quantification revealed no significant changes in CYP3A4 protein abundance between normoxic vs. hypoxic and non‐pregnant vs. pregnant sheep. Lastly, quantified total methylated cytosines (TMC) showed that, compared to their normoxic controls, LTH increased the TMC in non‐pregnant sheep (65%) but decreased (48%) the TMC in pregnant sheep. TMC was increased (38%) in pregnant compared to non‐pregnant normoxic sheep but decreased (56%) in pregnant compared to non‐pregnant hypoxic sheep. Together, these results suggest that gene silencing via CpG methylation of candidate CYP genes may contribute to changes in the catalytic activity of CYP3A4 during pregnancy but not non‐pregnant states.Support or Funding InformationLoma Linda University School of Pharmacy Faculty Scholarship Fund.NIH Program Project Grant from NICHD (HD31266) and an NIH R01 Grant from NINDS (NS076945).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.