Bartsch H, Rojas M, Alexandrov K, Camus A M, Castegnaro M, Malaveille C, Anttila S, Hirvonen K, Husgafvel-Pursiainen K, Hietanen E
German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg.
Pharmacogenetics. 1995;5 Spec No:S84-90. doi: 10.1097/00008571-199512001-00007.
A case-control study on lung cancer patients demonstrated the pronounced effect of tobacco smoke on pulmonary carcinogen metabolism and suggested the existence of a metabolic phenotype at higher risk for tobacco-associated lung cancer. Lung cancer patients who were recent smokers showed in their lungs (i) significantly induced CYP1A1-related enzyme activity vs smoking non-lung cancer patients; (ii) increased benzo(a)pyrene (BP) tetrol formation from BP 7,8-diol by lung microsomes; and (iii) high levels of cytochrome P4501a1 by immunohistochemical staining. Levels of bulky aromatic DNA adducts (by 32P-postlabelling) and of BP-diol-epoxide (BPDE) adducts (by HPC/fluorometry) were quantified in lung parenchyma. Aryl hydrocarbon hydroxylase activity and the level of BPDE-DNA adducts (r = 0.91; p < 0.001) and to a lesser degree bulky DNA adducts were correlated. Thus pulmonary CYP1A1 expression (inducibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk. High risk subjects for lung cancer among smokers may be identifiable through genotyping for polymorphic drug metabolizing enzymes in combination with molecular dosimetry of carcinogen-DNA adducts and mutation analysis in target (surrogate) cells. Such studies in a Finnish cohort of lung cancer patients and controls are in progress. Interim results of the effect of metabolic polymorphism on the level of PAH-DNA adducts and on the excretion of mutagens in urine are summarized.
一项针对肺癌患者的病例对照研究表明，烟草烟雾对肺部致癌物代谢有显著影响，并提示存在一种代谢表型，其患烟草相关肺癌的风险更高。近期吸烟的肺癌患者肺部表现出：（i）与吸烟的非肺癌患者相比，CYP1A1相关酶活性显著诱导；（ii）肺微粒体使苯并(a)芘（BP）7,8 -二醇生成BP四醇增加；（iii）免疫组化染色显示细胞色素P4501a1水平较高。对肺实质中大分子芳香族DNA加合物（通过32P后标记法）和BP -二醇环氧化物（BPDE）加合物（通过高效液相色谱/荧光法）水平进行了定量。芳烃羟化酶活性与BPDE - DNA加合物水平（r = 0.91；p < 0.001）以及程度较轻的大分子DNA加合物相关。因此，肺部CYP1A1表达（诱导性）部分控制吸烟者多环芳烃 - DNA加合物的形成，所以似乎与肺癌风险相关。吸烟者中肺癌高危个体可通过对多态性药物代谢酶进行基因分型，结合致癌物 - DNA加合物的分子剂量测定和靶（替代）细胞中的突变分析来识别。芬兰一组肺癌患者和对照的此类研究正在进行中。总结了代谢多态性对PAH - DNA加合物水平及尿液中诱变剂排泄影响的中期结果。
