Rannug A, Alexandrie A K, Persson I, Ingelman-Sundberg M
Department of Toxicology, National Institute of Occupational Health, Solna, Sweden.
J Occup Environ Med. 1995 Jan;37(1):25-36. doi: 10.1097/00043764-199501000-00005.
Because of important roles of cytochromes P450 in the metabolic activation of many precarcinogens, extensive research in the past has focused on the relationship between the distribution of polymorphic variants of different isozymes of P450 and cancer susceptibility. In this respect three isozymes in particular have been studied, CYP1A1, CYP2D6, and CYP2E1. Both CYP1A1 and CYP2E1 participate in the metabolism of many suspected as well as established carcinogens, whereas essentially only one carcinogenic substrate has been identified for CYP2D6. Polymorphic sites for the three CYP genes have been identified both in the open reading frame as well as in introns and the regulatory 5' region. In the present contribution we summarize the molecular epidemiological research relating CYP polymorphism to cancer susceptibility and in some cases to toxicity. An interesting polymorphism has been described on the phenotypic level for the inducibility of CYP1A1, a polymorphism that in some studies has been related to a mutation in the 3' flanking region of the CYP1A1 gene. However, the genetic basis for this polymorphism might be inherited in the genes coding for proteins responsible for the induction of CYP1A1, ie, the Ah receptor or the ARNT protein. Data on lung cancer and CYP1A1 gene polymorphism indicate that carriers of genotypes associated with CYP1A1 inducibility are at higher risk for cancer, but that, at least for Caucasians, the recognized mutations probably identify only a fraction of the inducible individuals. The amount of DNA adducts correlates well in some studies to the individual activity registered for CYP1A1. CYP2D6 phenotype and genotype have mainly been related to the incidence of lung cancer, but results from 13 different studies now show an absence of any significant correlation between these parameters. In the case of CYP2E1, some studies indicate a relationship between lung cancer and the occurrence of a rare allele, although future research is needed in order to establish a significant relationship. It is concluded that, at the present stage, none of the polymorphic sites determined in the CYP genes can yet be used as markers for increased lung cancer risk. Future research in this field might be focused on the establishment of new polymorphic sites in the CYP genes, affecting inducibility or function, and on the molecular basis for the interesting differences in CYP1A1 inducibility.
由于细胞色素P450在许多前致癌物的代谢活化中起着重要作用，过去广泛的研究集中在P450不同同工酶的多态性变体分布与癌症易感性之间的关系上。在这方面，特别研究了三种同工酶，即CYP1A1、CYP2D6和CYP2E1。CYP1A1和CYP2E1都参与许多可疑致癌物以及已确定致癌物的代谢，而对于CYP2D6，基本上只鉴定出一种致癌底物。这三种CYP基因的多态性位点已在开放阅读框以及内含子和调控性5'区域中被鉴定出来。在本论文中，我们总结了将CYP多态性与癌症易感性以及某些情况下与毒性相关的分子流行病学研究。在表型水平上已经描述了CYP1A1诱导性的一种有趣的多态性，在一些研究中这种多态性与CYP1A1基因3'侧翼区域的突变有关。然而，这种多态性的遗传基础可能是由编码负责诱导CYP1A1的蛋白质的基因遗传而来，即芳烃受体或ARNT蛋白。关于肺癌和CYP1A1基因多态性的数据表明，与CYP1A1诱导性相关基因型的携带者患癌症的风险更高，但至少对于白种人来说，已识别的突变可能仅识别出一部分可诱导个体。在一些研究中，DNA加合物的量与为CYP1A1记录的个体活性密切相关。CYP2D6的表型和基因型主要与肺癌的发病率相关，但来自13项不同研究的结果现在表明这些参数之间不存在任何显著相关性。就CYP2E1而言，一些研究表明肺癌与一种罕见等位基因的出现之间存在关系，尽管为了确定显著关系还需要进一步的研究。结论是，在现阶段，CYP基因中确定的任何多态性位点都还不能用作肺癌风险增加的标志物。该领域未来的研究可能集中在确定CYP基因中影响诱导性或功能的新多态性位点，以及CYP1A1诱导性有趣差异的分子基础上。
