Effects of hypothermia and hypoxia on cytochrome P450-mediated drug metabolism in neonatal Göttingen minipigs

Abstract

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. As perinatal asphyxia and TH impact neonatal physiology, this could also influence enzyme functionality. Therefore, this study aimed to unravel the impact of age, hypothermia and hypoxia on porcine hepatic cytochrome P450 (CYP) gene expression, protein abundance and activity. Hepatic CYP expression, protein abundance and activity were assessed in naive adult and neonatal Göttingen minipigs, alongside those from an (non-survival) in vivo study, where four conditions—control (C), therapeutic hypothermia (TH), hypoxia (H), hypoxia and TH (H + TH)—were examined. Naive neonatal Göttingen minipigs exhibited 75% lower general CYP activity and different gene expression patterns than adults. In vitro hypothermia (33°C) decreased general CYP activity in adult liver microsomes by 36%. Gene expression was not different between TH and C while hypoxia up-regulated several genes (i.e., CYP3A29 [expression ratio; E_R = 5.1472] and CYP2C33 [E_R = 3.2292] in the H group and CYP2C33 [E_R = 2.4914] and CYP2C42 [E_R = 4.0197] in the H + TH group). The medical treatment and the interventions over 24 h, along with hypoxia and TH, affected the protein abundance. These data on CYP expression, abundance and activity in young animals can be valuable in building physiologically-based pharmacokinetic models for neonatal drug dose predictions.