Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism
Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism
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DOI：
10.1073/pnas.93.4.1671
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发表时间：
1996-02-20
影响因子：
11.1
通讯作者：
Nebert, DW
中科院分区：
文献类型：
--
作者：
Liang, HCL;Li, H;Nebert, DW
细胞色素P450 1A2(CYP1A2)是一种以肝脏为主的酶，在许多具有药理、毒理和致癌意义的外来化学物质的代谢中起重要作用。CYP1A2底物包括黄曲霉毒素B-1、对乙酰氨基酚和各种环境芳胺。为了更好地确定该酶的发育和代谢功能，我们通过胚胎干细胞的同源重组培育了一株CYP1A2缺陷的小鼠。纯合靶向的CYP1A2基因的小鼠，命名为CYP1A2(-/-)，是完全存活和可育的；对15天的胚胎、新生的幼鼠和3周大的小鼠进行的组织学检查显示没有异常。Northern印迹分析未检测到细胞色素P1A2基因的表达。此外，同一亚家族中的另一个基因Cyp1a1的mRNA水平似乎不受CYP1A2基因缺失的影响。由于肌肉松弛药唑唑胺是CYP1A2的已知底物，我们通过唑唑拉明麻痹试验研究了CYP1A2(-/-)基因：与CYP1A2(+/+)野生型动物相比，CYP1A2(-/-)小鼠的瘫痪时间显著延长，并且CYP1A2(+/-)杂合子显示出中间效应。一个可存活和可生育的CYP1A2缺陷小鼠品系的可获得性将为希望确定CYP1A2在众多代谢和药代动力学过程中的确切作用的研究人员提供一个有价值的工具。
Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known to be important in the metabolism of numerous foreign chemicals of pharmacologic, toxicologic, and carcinogenic significance. CYP1A2 substrates include aflatoxin B-1, acetaminophen, and a variety of environmental arylamines. To define better the developmental and metabolic functions of this enzyme, we developed a CYP1A2-deficient mouse line hy homologous recombination in embryonic stem cells. Mice homozygous for the targeted Cyp1a2 gene, designated Cyp1a2(-/-), are completely viable and fertile; histologic examination of 15-day embryos, new-born pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate for CYP1A2, we studied the Cyp1a2(-/-) genotype by using the zoxazolamine paralysis test: the Cyp1a2(-/-) mice exhibited dramatically lengthened paralysis times relative to the Cyp1a2(+/+) wild-type animals, and the Cyp1a2(+/-) heterozygotes showed an intermediate effect. Availability of a viable and fertile CYP1A2-deficient mouse line will provide a valuable tool for researchers wishing to define the precise role of CYP1A2 in numerous metabolic and pharmacokinetic processes.