Transgenic humanized mice carrying the human CYP1A1‐luc promoter show augmented transcriptional activation and increased susceptibility to lung damage by hyperoxia

Abstract

Supplemental oxygen administration is administered to infants having pulmonary insufficiency. In this study, we tested the hypothesis that hyperoxia induces human cytochrome P450 (CYP)1A1 enzyme by transcriptional activation of the CYP1A1 promoter in vivo, and humanized mice expressing the human CYP1A1 promoter would be more susceptible to hyperoxic lung injury than those on a wild type (WT) background. Adult CD‐1 (8 week‐old) mice, transgenic mice carrying the human CYP1A1 promoter and the luciferase (luc) reporter gene on a WT or Cyp1a1‐null background (humanized) were maintained in room air or exposed to hyperoxia ( 24–72 h). Hyperoxia exposure of mice expressing hCYP1A1 promoter for 24 and 48 h resulted in 3‐ and 1.9‐fold increases, respectively in luc signal intensities, compared to room air controls, and humanized mice showed a greater extent of induction, suggesting that CYP1A1 metabolizes endogenous Ah receptor ligands. The hCYP1A1‐luc mice showed the greater susceptibility to lung injury than WT mice, and this was potentiated in humanized mice, suggesting that endogenous Cyp1a1 enzyme is protective against injury. (Supported by grants RO1HL070921 and RO1HL087174.)