NEONATAL LETHALITY ASSOCIATED WITH RESPIRATORY-DISTRESS IN MICE LACKING CYTOCHROME-P450 1A2
NEONATAL LETHALITY ASSOCIATED WITH RESPIRATORY-DISTRESS IN MICE LACKING CYTOCHROME-P450 1A2
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DOI：
10.1073/pnas.92.11.5134
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发表时间：
1995-05-23
影响因子：
11.1
通讯作者：
GONZALEZ, FJ
中科院分区：
文献类型：
--
作者：
PINEAU, T;FERNANDEZSALGUERO, P;GONZALEZ, FJ
细胞色素P450 1A 2（CYP 1A 2）是一种组成型表达的肝酶，在哺乳动物中高度保守。这种蛋白质主要参与外源性物质的氧化代谢，并能够代谢活化多种前致癌物，包括黄曲霉毒素B1、芳胺、杂环胺食品诱变剂和多环芳烃。CYP 1A 2的表达在暴露于某些芳烃（即，2，3，7，8-四氯二苯并对二恶英）。尚未记录CYP 1A 2在任何生理或发育途径中作用的直接证据。我们现在证明，在Cyp 1a-2基因的靶向突变纯合子小鼠是不能生存的。致命性发生在出生后不久，伴有严重呼吸窘迫症状。突变的新生儿表现出与肺不成熟的组织学体征相关的呼吸功能受损，出生时肺泡中缺乏空气，以及肺泡II型细胞中表面活性剂载脂蛋白表达的变化。表型的突变并不完全（599只小鼠中有19只突变体存活至成年）。存活的动物，虽然缺乏CYP 1A 2的表达，但似乎是正常的，并且能够繁殖。这些研究结果表明，CYP 1A 2是通过影响新生儿呼吸生理的新生儿生存的关键，从而提供新生儿呼吸窘迫综合征的病因学见解。
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.