Omeprazole Attenuates Hyperoxic Lung Injury in Mice via Aryl Hydrocarbon Receptor Activation and Is Associated with Increased Expression of Cytochrome P4501A Enzymes

Abstract

Hyperoxia contributes to lung injury in experimental animals and bronchopulmonary dysplasia (BPD) in preterm infants. Cytochrome P4501A (CYP1A) enzymes, which are regulated by the aryl hydrocarbon receptor (AhR), have been shown to attenuate hyperoxic lung injury in rodents. Omeprazole, a proton pump inhibitor, used in humans to treat gastric acid-related disorders, induces hepatic CYP1A in vitro. However, the mechanism by which omeprazole induces CYP1A and its impact on CYP1A expression in vivo and hyperoxic lung injury are unknown. Therefore, we tested the hypothesis that omeprazole attenuates hyperoxic lung injury in adult wild-type (WT) C57BL/6J mice by an AhR-mediated induction of pulmonary and hepatic CYP1A enzymes. Accordingly, we determined the effects of omeprazole on pulmonary and hepatic CYP1A expression and hyperoxic lung injury in adult WT and AhR dysfunctional (AhRd) mice. We found that omeprazole attenuated lung injury in WT mice. Attenuation of lung injury by omeprazole paralleled enhanced pulmonary CYP1A1 and hepatic CYP1A2 expression in the omeprazole-treated mice. On the other hand, omeprazole failed to enhance pulmonary CYP1A1 and hepatic CYP1A2 expression and protect against hyperoxic lung injury in AhRd mice. In conclusion, our results suggest that omeprazole attenuates hyperoxic lung injury in mice by AhR-mediated mechanisms, and this phenomenon is associated with induction of CYP1A enzymes. These studies have important implications for the prevention and/or treatment of hyperoxia-induced disorders such as BPD in infants and acute respiratory distress syndrome in older children and adults.

338: Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury

“…Furthermore, recent studies have demonstrated an attenuating effect of CYP1A1 inducers on hyperoxic lung injury both in vitro [10,24] as well as in vivo [11][12][13].…”

“…Transplacental transfer is present but low, and dependent on the maternal plasma levels [23]. To our knowledge the use of omeprazole in preventing hyperoxia induced lung injury has only been demonstrated so far in vitro [24] and in in vivo mice models [12,25]. Herein, we test the hypothesis that in a hyperoxic induced lung injury preterm rabbit model, prenatal or neonatal administration of omeprazole (1) induces transcription of CYP1A1 in a dose-dependent way and (2) improves pulmonary outcome both on histological as well as functional level.…”

“…In recent years, the importance of cytochrome P450 enzymes as well as the aryl hydrocarbon receptor (AhR) has been demonstrated in the metabolism of a number of endogenous and exogenous compounds as well as for oxygen-induced toxicity [10][11][12][13]. When a ligand binds, AhR is translocated to the nucleus, where it dimerizes with the aryl hydrocarbon nuclear translocator (ARNT).…”

“…CYP1A1 is typically induced by planar aromatic hydrocarbons (PAH), but hyperoxia can also induce CYP1A1 [10,15]. The exact mechanism of induction is unknown, but the AhR seems to play an important role as AhR [10,12,13] or CYP1A1 [16] deficient mice react differently on hyperoxic exposure. The induction by hyperoxia decreases if it continues for over 60 h in adult mice models [4,17].…”

Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor

“…Studies from our and other laboratories have reported that AhR and its downstream target, CYP1A enzymes, may be a crucial regulator of pulmonary and hepatic oxidant stress and inflammation in mice through the induction of several detoxifying enzymes or via "cross-talk" with other signal transduction pathways (Jiang et al, 2004;Thatcher et al, 2007;Baglole et al, 2008; Rico de dmd.aspetjournals.org Souza et al, 2011;Shivanna et al, 2011bShivanna et al, , 2013. However, the prototypical inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and MC are unsuitable for clinical use because of their well known toxicities.…”