Ontogeny of Novel Cytochrome P450 Gene Isoforms during Postnatal Liver Maturation in Mice
Ontogeny of Novel Cytochrome P450 Gene Isoforms during Postnatal Liver Maturation in Mice
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DOI：
10.1124/dmd.111.042697
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发表时间：
2012-06-01
影响因子：
3.9
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
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作者：
Cui, Julia Yue;Renaud, Helen J.;Klaassen, Curtis D.
细胞色素P450（P450 s）的前四个家族的个体发育（即，Cyp 1-Cyp 4）可影响药物和膳食化学品在肝脏中的生物转化，导致儿童独特的药理学反应。由于基因组规模的研究已经确定了许多新的P450亚型，因此在肝脏发育过程中对这些P450进行系统表征至关重要。在该研究中，在出生前2天和在不同的出生后年龄（0-45日龄）从C57 BL/6小鼠收集肝脏。用分支DNA分析和逆转录-聚合酶链反应测定75种P450亚型（Cyp 1-Cyp 4）的mRNA水平。超过一半的小鼠P450在人类中是保守的，但在小鼠中有更多的同种型。P450 mRNA水平在出生后小鼠肝脏中增加，形成四种不同的个体发育模式。大多数P450形成总共8个基因组簇，即9号染色体上的Cyp 1a 1和Cyp 1a 2基因（簇1），Cyp 2a、Cyp 2b、Cyp 2f、Cyp 2g和Cyp 2 t基因在7号染色体上（簇2），Cyp 2c基因在染色体19上（簇3），Cyp 2d基因在15号染色体上（簇4），Cyp 2 j基因在染色体4上（簇5），染色体5上的Cyp 3a基因（簇6），染色体4上的Cyp 4a、Cyp 4 b和Cyp 4x基因（簇7），和染色体17上的Cyp 4f基因（簇8）。同一基因组簇内的一些P450亚型表现出相似的个体发育模式。总之，本研究揭示了肝脏中P450的四种个体发育模式，并表明基因组簇内的许多P450表现出相似的个体发育模式，这表明簇内的一些P450可能在肝脏发育过程中受到共同途径的调控。
The ontogeny of the first four families of cytochromes P450 (P450s) (i.e., Cyp1-Cyp4) can affect the biotransformation of drugs and dietary chemicals in liver, resulting in unique pharmacological reactions in children. Because genome-scale investigations have identified many novel P450 isoforms, it is critical to perform a systematic characterization of these P450s during liver development. In this study, livers were collected from C57BL/6 mice 2 days before birth and at various postnatal ages (0-45 days of age). The mRNA levels for 75 P450 isoforms (Cyp1-Cyp4) were quantified with branched DNA assays and reverse transcription-polymerase chain reaction assays. More than half of the mouse P450s are conserved in humans, but there are more isoforms in mice. The P450 mRNA levels increased after birth in mouse liver, forming four distinct ontogenic patterns. The majority of P450s form a total of eight genomic clusters, namely, Cyp1a1 and Cyp1a2 genes on chromosome 9 (cluster 1), Cyp2a, Cyp2b, Cyp2f, Cyp2g, and Cyp2t genes on chromosome 7 (cluster 2), Cyp2c genes on chromosome 19 (cluster 3), Cyp2d genes on chromosome 15 (cluster 4), Cyp2j genes on chromosome 4 (cluster 5), Cyp3a genes on chromosome 5 (cluster 6), Cyp4a, Cyp4b, and Cyp4x genes on chromosome 4 (cluster 7), and Cyp4f genes on chromosome 17 (cluster 8). Some P450 isoforms within the same genomic cluster showed similar ontogenic patterns. In conclusion, the present study revealed four patterns of ontogeny for P450s in liver and showed that many P450s within a genomic cluster exhibited similar ontogenic patterns, which suggests that some P450s within a cluster are likely regulated by a common pathway during liver development.