Micka J, Milatovich A, Menon A, Grabowski G A, Puga A, Nebert D W
Physician Scientist Training Program, CHRF, Cincinnati, OH 45229, USA.
Pharmacogenetics. 1997 Apr;7(2):95-101. doi: 10.1097/00008571-199704000-00002.
The mammalian aromatic hydrocarbon receptor (AHR) is a ubiquitous ligand-activated transcription factor. AHR ligands include 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), benzo[a]pyrene, and polychlorinated and polybrominated biphenyls; the endogenous ligand is not yet known. Following ligand binding, the AHR transcriptionally activates genes encoding drug-metabolizing enzymes important in both the metabolic potentiation of substrates to genotoxic reactive intermediates and ultimate carcinogens, and the detoxification of toxic or carcinogenic drugs and other environmental pollutants. AHR-mediated gene expression is also involved in many critical life processes (e.g. cell type-specific differentiation, cell division, apoptosis) by signal transduction mechanisms. Similar to mice, human populations exhibit a > 20-fold range of the CYP1A1 inducibility/AHR affinity phenotype. In the present study, we localized the human AHR gene to chromosome 7p15, using fluorescence in situ hybridization (FISH). Performing linkage analysis in a three-generation family, we show with good probability that the high CYP1A1 inducibility phenotype segregates with the 7p15 region. Sequencing 93 nt (31 amino acids) of the human AHR gene's exon 9, which is the region correlated with the mouse A375V polymorphism responsible for the major portion of high vs low CYP1A1 inducibility/AHR affinity, we found no nucleotide differences; Val-381 was present in all five individuals examined (four related and one unrelated), two of whom show "high' and three of whom show "low' CYP1A1 inducibility. These data indicate that the "high' and "low' CYP1A1 inducibility trait, in the population studied, cannot be explained by a difference among these 31 amino acids in exon 9 of the AHR gene.
哺乳动物芳香烃受体（AHR）是一种普遍存在的配体激活转录因子。AHR配体包括2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD；二恶英）、苯并[a]芘以及多氯联苯和多溴联苯；内源性配体尚不清楚。配体结合后，AHR转录激活编码药物代谢酶的基因，这些酶在底物代谢增强为遗传毒性反应性中间体和最终致癌物以及有毒或致癌药物及其他环境污染物的解毒过程中都很重要。AHR介导的基因表达还通过信号转导机制参与许多关键的生命过程（如细胞类型特异性分化、细胞分裂、细胞凋亡）。与小鼠相似，人类群体中CYP1A1诱导性/AHR亲和力表型的范围超过20倍。在本研究中，我们使用荧光原位杂交（FISH）将人类AHR基因定位到7号染色体p15区域。在一个三代家族中进行连锁分析，我们很有可能地表明高CYP1A1诱导性表型与7p15区域共分离。对人类AHR基因外显子9的93个核苷酸（31个氨基酸）进行测序，该区域与小鼠中负责大部分高与低CYP1A1诱导性/AHR亲和力的A375V多态性相关，我们未发现核苷酸差异；在所检测的所有五个人（四个有亲缘关系和一个无亲缘关系）中均存在缬氨酸381，其中两人表现出“高”CYP1A1诱导性，三人表现出“低”CYP1A1诱导性。这些数据表明，在所研究的人群中，“高”和“低”CYP1A1诱导性特征不能用AHR基因外显子9中这31个氨基酸的差异来解释。
