Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Abstract

Hyperoxia contributes to acute lung injury (ALI) in diseases such as acute respiratory distress syndrome (ARDS). Cytochrome P450 (CYP)1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role(s) of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene for Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia, and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight to ten week old WT (C57BL/6) or Cyp1a2(−/−) mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24–72 h. Lung injury was assessed by determining the ratios of lung weight/body weight (LW/BW), and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2(−/−) mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, IL-6 and TNF-α levels, and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde (MDA)- and 4-hydroxynonenal (4-HNE)-protein adducts, and pulmonary isofurans compared to those of WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation against hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.

Leflunomide induces NAD(P)H quinone dehydrogenase 1 enzyme via the aryl hydrocarbon receptor in neonatal mice

“…The protective effects of CYP1A enzymes against hyperoxia-induced lung injury in rodents have been extensively documented [26, 41–43]. In addition, NQO1 has been shown to protect cells and tissues against oxidant injury induced by various toxic chemicals [44] and oxygen [45].…”

Antioxidant Functions of the Aryl Hydrocarbon Receptor

“…Also, circulating F 2 -isoprostanes are considered to play a role in inflammatory lung diseases by various receptor-triggered pathways (for review, see [91]). In a recent work by Wang and coworkers [92], it was shown that knocking out Cyp1a2, primarily expressed in the liver, also increased susceptibility for hyperoxic lung injury. This was assessed by the ratio weight lung /weight body and histology, pulmonary neutrophil infiltration, cytokine expression, lipid peroxidation, and F 2 -isoprostane levels in liver and lung [92].…”

“…In a recent work by Wang and coworkers [92], it was shown that knocking out Cyp1a2, primarily expressed in the liver, also increased susceptibility for hyperoxic lung injury. This was assessed by the ratio weight lung /weight body and histology, pulmonary neutrophil infiltration, cytokine expression, lipid peroxidation, and F 2 -isoprostane levels in liver and lung [92]. The authors finally provide evidence for CYP1A2-mediated metabolism of PGF 2 - α in vitro supporting the idea that CYP1A1 and CYP1A2 protect against oxidative stress by decreasing the amount of lung- or liver-derived circulating F 2 -isoprostanes.…”

The mechanism of Psoralen and Isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats

“…Cytochrome P450 metabolism of Xenobiotics pathway contains 7 intersection genes that include Cyp1a1, Cyp1a2 and Gstm1, which might be the most related pathway to hepatotoxicity induced by psoralen and isopsoralen. CYP450s, as the primary enzymes for phase I drug metabolism, involved in the metabolism of various exogenous and endogenous compounds . Another important pathway impacted by psoralen and isopsoralen was Chemical Carcinogenesis because Cyp1a1, Cyp1a2, Ephx1, Gstm1 and Aldh3a1 all involved in this.…”