Savkur Rajesh S, Wu Yifei, Bramlett Kelli S, Wang Minmin, Yao Sufang, Perkins Douglas, Totten Michelle, Searfoss George, Ryan Timothy P, Su Eric W, Burris Thomas P
Gene Regulation Research, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):216-26. doi: 10.1016/j.ymgme.2003.08.013.
The human constitutive androstane receptor (hCAR; NR1I3) is a member of the nuclear receptor superfamily. The activity of hCAR is regulated by a variety of xenobiotics including clotrimazole and acetaminophen metabolites. hCAR, in turn, regulates a number of genes responsible for xenobiotic metabolism and transport including several cytochrome P450s (CYP 2B5, 2C9, and 3A4) and the multidrug resistance-associated protein 2 (MRP2, ABCC2). Thus, hCAR is believed to be a mediator of drug-drug interactions. We identified two novel hCAR splice variants: hCAR2 encodes a receptor in which alternative splice acceptor sites are utilized resulting in a 4 amino acid insert between exons 6 and 7, and a 5 amino acid insert between 7 and 8, and hCAR3 encodes a receptor with exon 7 completely deleted resulting in a 39 amino acid deletion. Both hCAR2 and hCAR3 mRNAs are expressed in a pattern similar to the initially described MB67 (hCAR1) with some key distinctions. Although the levels of expression vary depending on the tissue examined, hCAR2 and hCAR3 contribute 6-8% of total hCAR mRNA in liver. Analysis of the activity of these variants indicates that both hCAR2 and hCAR3 lose the ability to heterodimerize with RXR and lack transactivation activity in cotransfection experiments where either full-length receptor or GAL4 DNA-binding domain/CAR ligand binding domain chimeras were utilized. Although the role of hCAR2 and hCAR3 is currently unclear, these additional splice variants may provide for increased diversity in terms of responsiveness to xenobiotics.
人组成型雄烷受体（hCAR；NR1I3）是核受体超家族的成员。hCAR的活性受多种异生素调节，包括克霉唑和对乙酰氨基酚代谢物。反过来，hCAR调节许多负责异生素代谢和转运的基因，包括几种细胞色素P450（CYP 2B5、2C9和3A4）以及多药耐药相关蛋白2（MRP2，ABCC2）。因此，hCAR被认为是药物相互作用的介质。我们鉴定出两种新的hCAR剪接变体：hCAR2编码一种受体，其中利用了替代剪接受体位点，导致外显子6和7之间插入4个氨基酸，7和8之间插入5个氨基酸；hCAR3编码一种受体，其外显子7完全缺失，导致39个氨基酸缺失。hCAR2和hCAR3的mRNA均以与最初描述的MB67（hCAR1）相似的模式表达，但有一些关键区别。尽管表达水平因所检测的组织而异，但hCAR2和hCAR3在肝脏中占hCAR总mRNA的6 - 8%。对这些变体活性的分析表明，在共转染实验中，无论是使用全长受体还是GAL4 DNA结合域/CAR配体结合域嵌合体，hCAR2和hCAR3都失去了与RXR异源二聚化的能力，并且缺乏反式激活活性。尽管hCAR2和hCAR3目前的作用尚不清楚，但这些额外的剪接变体可能在对外源生物的反应性方面提供更大的多样性。
