title: Sex-specific differences in hyperoxic lung injury in mice: role of cytochrome P450 (CYP)1A.
abstract: Sex-specific differences in pulmonary morbidity in adults and preterm infants are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. Cytochrome P450 (CYP) 1A enzymes have been shown to play a mechanistic role in hyperoxic lung injury (HLI) in animal models. Whether CYP1A enzymes contribute to gender-specific differences in relation to HLI is unknown. In this investigation, we tested the hypothesis that mice will display gender-specific differences in HLI, and that this phenomenon will be altered in mice lacking the genes for Cyp1a1 or 1a2. Eight week-old male and female wild type (WT) (C57BL/6J) mice, Cyp1a1-/-, and Cyp1a2-/- mice were exposed to 72h of hyperoxia (FiO2>0.95). Lung injury and inflammation were assessed and pulmonary and hepatic CYP1A1 and CYP1A2 levels were quantified at the enzyme activity, protein and mRNA level. Upon exposure to hyperoxia, liver and lung microsomal proteins showed higher pulmonary CYP1A1 (apoprotein level and activity) in WT females compared to WT males and a greater induction in hepatic CYP1A2 mRNA levels and activity in WT females after hyperoxia exposure. The gender based female advantage was lost or reversed in Cyp1a1-/- and Cyp1a2-/- mice. These findings suggest an important role for CYP1A enzymes in the gender-specific modulation of hyperoxic lung injury.
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. Electronic address: lingappa@bcm.edu.
authors.forename: Krithika
authors.initials: K
authors.lastname: Lingappan
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weiwu
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xanthi I
authors.initials: XI
authors.lastname: Couroucli
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
mesh_terms: D000818:Animals; D001835:Body Weight; D019363:Cytochrome P-450 CYP1A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D018496:Hyperoxia / Q000150:complications*; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2
keywords: CYP1A; Hyperoxia; Lung injury; Sex-specific