Neonatal Lethality Associated with Respiratory Distress in Mice Lacking Cytochrome P450 1A2

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-05, Vol.92 (11), p.5134-5138
• Main Authors: Pineau, Thierry, Fernandez-Salguero, Pedro, Susanna S. T. Lee, McPhail, Timothy, Ward, Jerrold M., Gonzalez, Frank J.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Biochemistry; Cellular Biology; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - deficiency; Cytochrome P-450 Enzyme System - genetics; Cytochromes; Death; Embryo, Mammalian; Embryonic stem cells; Enzyme Induction; Enzymes; Exons; Gallbladder - pathology; Genomics; Humans; Infant, Newborn; Life Sciences; Liver; Liver - enzymology; Liver - pathology; Lung - enzymology; Lung - pathology; Lungs; Mammals; Mice; Mice, Mutant Strains; Mutation; Newborns; Oxidoreductases - biosynthesis; Oxidoreductases - deficiency; Oxidoreductases - genetics; Phenotype; Phenotypes; Pulmonary Alveoli - pathology; Recombination, Genetic; Respiratory distress; Respiratory Distress Syndrome, Newborn - enzymology; Respiratory Distress Syndrome, Newborn - genetics; Respiratory Distress Syndrome, Newborn - pathology; Respiratory system; Restriction Mapping; Rodents; Stem Cells - cytology; Stem Cells - physiology; Thyroid Gland - enzymology; Thyroid Gland - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.11.5134

Cytochrome P450 1A2 (CYP1A2) is a constitutively expressed hepatic enzyme that is highly conserved among mammals. This protein is primarily involved in oxidative metabolism of xenobiotics and is capable of metabolically activating numerous procarcinogens including aflatoxin B1, arylamines, heterocyclic amine food mutagens, and polycylic aromatic hydrocarbons. Expression of CYP1A2 is induced after exposure to certain aromatic hydrocarbons (i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin). Direct evidence for a role of CYP1A2 in any physiological or developmental pathway has not been documented. We now demonstrate that mice homozygous for a targeted mutation in the Cyp1a-2 gene are nonviable. Lethality occurs shortly after birth with symptoms of severe respiratory distress. Mutant neonates display impaired respiratory function associated with histological signs of lung immaturity, lack of air in alveoli at birth, and changes in expression of surfactant apoprotein in alveolar type II cells. The penetrance of the phenotype is not complete (19 mutants survived to adulthood out of 599 mice). Surviving animals, although lacking expression of CYP1A2, appear to be normal and are able to reproduce. These findings establish that CYP1A2 is critical for neonatal survival by influencing the physiology of respiration in neonates, thus offering etiological insights for neonatal respiratory distress syndrome.