Rich K J, Boobis A R
MRC Toxicology Unit, University of Leicester, United Kingdom.
Microsc Res Tech. 1997 Dec 1;39(5):424-35. doi: 10.1002/(SICI)1097-0029(19971201)39:5<424::AID-JEMT5>3.0.CO;2-G.
Several approaches, including immunoquantification of individual enzymes, profiling of substrate activities by immunoinhibition using highly specific polyclonal and monoclonal antibodies, and the estimation of corresponding mRNAs with nucleic acid probes, have been used to investigate the ontogeny of cytochromes P450 in livers of rodents and man. CYP1A1 is expressed very early in development in rodents, whereas most other enzymes either appear at or near birth (CYP2B, CYP2C23, and CYP3A) or between 2 and 4 weeks following birth (CYP2A, CYP2C6, CYP2C7, CYP2C11, CYP2C12, and CYP4A10). The constitutive expression of enzymes is subject to regulation by various transcriptional nuclear and/or hormonal factors (CYP2B and CYP2C) or in a sex-dependent manner (CYP2A, CYP2C11, CYP2C12, CYP3A, and CYP4A10). The enhanced sensitivity and specificity of immunocytochemical and in situ hybridisation studies have revealed differences, with age and xenobiotic treatment, in the intercellular expression of certain P450 enzymes of the liver. For example, in rats, the expression of CYP1A1 and 1A2 is differentially regulated at the level of the individual cell from as early as 24 hours before birth. The human foetal liver relative to rodents has a substantial level of CYP3A and also has the capacity to metabolise a greater repertoire of substrates. Evidence to date suggests that P450 enzymes in man are regulated in a manner similar to that in other animals. The balance between different individual enzymes of cytochrome P450 in foetuses and/or neonates is subject to modulation by xenobiotics, the consequences of which may lead to toxicologically compromised livers with respect to metabolic handling of certain substrates.
已经采用了多种方法来研究啮齿动物和人类肝脏中细胞色素P450的个体发生，这些方法包括对单个酶进行免疫定量、使用高度特异性的多克隆和单克隆抗体通过免疫抑制分析底物活性，以及用核酸探针估计相应的mRNA。CYP1A1在啮齿动物发育的早期就有表达，而大多数其他酶要么在出生时或出生前后出现（CYP2B、CYP2C23和CYP3A），要么在出生后2至4周出现（CYP2A、CYP2C6、CYP2C7、CYP2C11、CYP2C12和CYP4A10）。酶的组成型表达受到各种转录核因子和/或激素因子（CYP2B和CYP2C）的调节，或者以性别依赖的方式（CYP2A、CYP2C11、CYP2C12、CYP3A和CYP4A10）进行调节。免疫细胞化学和原位杂交研究提高的敏感性和特异性揭示了肝脏中某些P450酶的细胞间表达随年龄和异生物质处理而产生的差异。例如，在大鼠中，早在出生前24小时，CYP1A1和1A2的表达就在单个细胞水平上受到不同的调节。相对于啮齿动物，人类胎儿肝脏中CYP3A的水平较高，并且具有代谢更多种类底物的能力。迄今为止的证据表明，人类中的P450酶的调节方式与其他动物相似。胎儿和/或新生儿中细胞色素P450的不同个体酶之间的平衡会受到异生物质的调节，其后果可能导致肝脏在某些底物的代谢处理方面出现毒理学受损。
