De Flora S, Camoirano A, Bagnasco M, Bennicelli C, van Zandwijk N, Wigbout G, Qian G S, Zhu Y R, Kensler T W
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
J Cell Biochem Suppl. 1996;25:92-8.
Urinary genotoxicity assays measure the internal dose of genotoxic carcinogens, thereby providing a particularly sensitive endpoint for selecting cohorts of individuals exposed to cigarette smoke or other mutagens excreted with urines, as well as for evaluating the modulation of this parameter after administration of chemopreventive agents. Mutagenicity of urines was investigated in smoking Italian volunteers, who received oral N-acetylcysteine (NAC) at the same doses which are usually prescribed for the long-term treatment of chronic bronchitis. The daily excretion of mutagens, concentrated on XAD-2 columns and tested in Salmonella typhimurium YG1024 with S9 mix, was significantly and remarkably decreased by NAC in the majority of the subjects examined so far. Time-course experiments showed that this effect starts since the first day of drug administration and reverses when treatment is withdrawn. In addition, NAC administration almost totally prevented urinary genotoxicity in one subject whose concentrated urines induced a differential lethality in Escherichia coli strains having distinctive DNA repair capacities. The decrease of urinary genotoxicity produced by NAC in the majority of smokers correlates with the ability of this thiol to prevent tumors and to affect a variety of intermediate biomarkers in animal models. Modulation of the urinary excretion of mutagens is one of the biomarkers evaluated in two ongoing Phase II chemoprevention trials. One study involves the oral administration of NAC in Dutch smokers. The pretreatment urine samples of all the subjects so far recruited are clearly mutagenic. The other study involves the oral administration of the dithiolethione oltipraz to individuals living in the Qidong County of the People's Republic of China, an area of high endemy for HBV infection and of high exposure to aflatoxins. Additionally, a large proportion of the recruited male subjects are smokers. A total of 500 urine specimens will be assayed from 240 subjects according to a complex protocol arranged in three consecutive phases.
尿液遗传毒性检测可测量遗传毒性致癌物的体内剂量，从而为选择接触香烟烟雾或其他随尿液排出的诱变剂的个体队列提供一个特别敏感的终点指标，同时也可用于评估化学预防剂给药后该参数的调节情况。对吸烟的意大利志愿者的尿液诱变性进行了研究，这些志愿者接受了通常用于慢性支气管炎长期治疗的相同剂量的口服N-乙酰半胱氨酸（NAC）。通过XAD-2柱浓缩并在鼠伤寒沙门氏菌YG1024中与S9混合物一起检测的诱变剂的每日排泄量，在迄今为止检查的大多数受试者中，NAC使其显著且明显降低。时间进程实验表明，这种作用从给药的第一天就开始，停药后则逆转。此外，在一名其浓缩尿液在具有不同DNA修复能力的大肠杆菌菌株中诱导差异致死率的受试者中，NAC给药几乎完全预防了尿液遗传毒性。NAC在大多数吸烟者中导致的尿液遗传毒性降低与该硫醇在动物模型中预防肿瘤和影响多种中间生物标志物的能力相关。诱变剂尿液排泄的调节是两项正在进行的II期化学预防试验中评估的生物标志物之一。一项研究涉及在荷兰吸烟者中口服NAC。到目前为止招募的所有受试者的预处理尿液样本都明显具有诱变性。另一项研究涉及向中华人民共和国启东县的居民口服二硫代硫酮奥替普拉，启东县是乙肝病毒感染高发和黄曲霉毒素高暴露地区。此外，招募的男性受试者中有很大一部分是吸烟者。将根据一个安排在三个连续阶段的复杂方案，从240名受试者中检测总共500份尿液标本。
