Anttila S, Lei X D, Elovaara E, Karjalainen A, Sun W, Vainio H, Hankinson O
Department of Pathology and Laboratory Medicine and Johnson Comprehensive Cancer Center, University of California, Los Angeles, USA.
Pharmacogenetics. 2000 Nov;10(8):741-51. doi: 10.1097/00008571-200011000-00008.
Cigarette smoking can induce CYP1A1 in the lung. Induction requires the aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins. Lung samples from seven of 75 Finnish patients who smoked until the time of surgery exhibited absent or low levels of CYP1A1 protein, mRNA and enzymatic activity, suggesting that these individuals might be genetically non or poorly inducible for CYP1A1. All seven lung samples expressed normal levels of AHR mRNA and ARNT mRNA, indicating that they did not carry inactivating polymorphisms in the 5' upstream regulatory regions of these genes. Sequencing of cDNAs encompassing the complete coding regions of AHR and ARNT identified a previously known codon 554 polymorphism in AHR, which was present in the homozygous state in one individual. This polymorphism, which leads to an amino acid substitution, has previously been reported either to have no effect or to enhance CYP1A1 induction. Previously unreported silent single nucleotide polymorphisms were identified in codon 44 of AHR and codon 189 of ARNT. 1500 bp of genomic sequence from the 5' upstream regulatory sequence of the CYP1A1 gene was also sequenced in the non-inducible individuals. A nucleotide substitution polymorphism at position -459 was detected in the heterozygous state in two individuals. This polymorphic site does not reside in any known regulatory sequence. The complete CYP1A1 coding sequence and intron/exon boundaries were then sequenced. None of the non or poorly inducible individuals exhibited any polymorphisms, either homozygous or heterozygous compared to representative inducible individuals or the previously published CYP1A1 sequence. Thus, no polymorphisms in the AHR, ARNT or CYP1A1 genes were identified that could be responsible for the non/low inducibility phenotype observed.
吸烟可诱导肺组织中的CYP1A1。这种诱导作用需要芳烃受体（AHR）和芳烃受体核转运蛋白（ARNT）。75名芬兰患者中，有7名在手术前一直吸烟，其肺组织样本中CYP1A1蛋白、mRNA和酶活性缺失或水平较低，这表明这些个体可能在基因上对CYP1A1的诱导作用不敏感或诱导能力较差。所有7个肺组织样本中AHR mRNA和ARNT mRNA的表达水平正常，这表明它们在这些基因的5'上游调控区域没有携带失活的多态性。对包含AHR和ARNT完整编码区的cDNA进行测序，在AHR中发现了一个先前已知的密码子554多态性，该多态性在一名个体中呈纯合状态。这种导致氨基酸替代的多态性，先前的报道要么是没有影响，要么是增强CYP1A1的诱导作用。在AHR的密码子44和ARNT的密码子189中发现了先前未报道的沉默单核苷酸多态性。对诱导能力差的个体的CYP1A1基因5'上游调控序列的1500 bp基因组序列也进行了测序。在两名个体中检测到-459位核苷酸替代多态性，呈杂合状态。这个多态性位点并不存在于任何已知的调控序列中。然后对完整的CYP1A1编码序列和内含子/外显子边界进行测序。与有代表性的可诱导个体或先前发表的CYP1A1序列相比，诱导能力差或无诱导能力的个体均未表现出任何纯合或杂合的多态性。因此，未发现AHR、ARNT或CYP1A1基因中的多态性与所观察到的非诱导/低诱导表型有关。
