Biomonitoring of genotoxic exposure of aluminium plant workers.

Humans are environmentally and occupationally exposed to polycyclic aromatic hydrocarbons (PAH). PAH's are a class of tumorigenic compounds which act through metabolic transformation to chemically reactive forms, epoxides, which covalently bind to DNA forming DNA adducts. To evaluate the genotoxic effects of PAH's, air and urine samples were analyzed for PAH. Blood samples were analyzed for benzo(a)pyrene-diol-epoxide-DNA (BPDE-DNA) adducts. New methods for analyzing DNA adducts in lymphocytes have been used to study the genotoxic effects of human exposure to carcinogens. BPDE-DNA adducts in lymphocytes have been used as internal dosimeters of exposure to PAH's and several studies have been conducted. We measured BPDE-DNA adducts in aluminium plant workers with immuno-assay and physico-chemical methods. PAH-DNA adducts were detectable to a lesser extent in subjects working in an aluminium plant compared to subjects working in a coke oven plant.     

DNA adduct formation of benzo[a]pyrene in white blood cells of workers exposed to polycyclic aromatic hydrocarbons

The major DNA adducts of anti-benzo[a]pyrene diolepoxide (BPDE) were determined by high performance liquid chromatography with fluorescence detection (HPLC-FLD) in white blood cells (WBC) of workers exposed to benzo[a]pyrene (B[a]P). In addition, ambient concentrations of B[a]P at the workplace were determined by personal air sampling. Workers in a refractory setting were examined before (n=26) and 3 months after (n = 33) changing the production material (binding pitch). Furthermore, 9 coke oven workers were examined. The change in the production process in the refractory setting led to a decrease in the median of ambient B[a]P concentrations (0.14 to <0.07 microg/m3). The median of BPDE-DNA adduct levels in WBC also decreased from 0.9 adducts/10(8) nucleotides before changing the production material to <0.5 adducts/10(8) nucleotides 3 months afterwards. The B[a]P concentrations at the workplace for the coke oven workers were found to be significantly higher than in the refractory setting. However, BPDE-DNA adduct concentrations in coke oven workers and refractory setting workers showed no significant difference, which was probably due to the low number of studied subjects in the coke-oven setting. No significant differences could be observed for BPDE-DNA adduct levels between current smokers (n=21) and non-smokers (n=14; p = 0.93) from both plants. In addition, no correlation between B[a]P concentrations in the air and DNA adduct levels in refractory workers and in coke oven workers could be found (r = -0.03, p = 0.87). Because of the missing correlation between personal air sampling and BPDE-DNA adduct levels in WBC, the results may indicate that their formation is either influenced by other routes of exposure to B[a]P (e.g., skin absorption, dietary habits) or interindividual differences in their formation and repair.     

Interaction of benzo[a]pyrene with other risk factors in hepatocellular carcinoma: a case-control study in Xiamen,China

PurposeLarge epidemiologic studies about the relationship between benzo[a]pyrene (B[a]P) and hepatocellular carcinoma (HCC) have been limited. B[a]P diol epoxide (BPDE) is a highly reactive metabolite of B[a]P that binds covalently to form DNA adducts. We evaluated the interaction between B[a]P exposure with other risk factors in HCC, in a case-control study of 345 HCC and 961 healthy controls.MethodsConcentration of BPDE-DNA adducts in blood was determined by enzyme-linked immunosorbent assay. The interaction between BPDE-DNA adducts and other risk factors on HCC were evaluated by multivariate logistic regression analysis.ResultsMean concentration of BPDE-DNA adducts in blood of cases was significantly higher than that of the controls. The risk of HCC increased with elevated concentration of BPDE-DNA adducts (x² = 203.57, P_trend < .001) and the odds ratio was 7.44 (95% confidence interval, 5.29–10.45) for the first versus fourth quartile of adduct levels. The relative excess risk due to interaction between BPDE-DNA adducts and hepatitis B virus surface antigen and drinking was 34.71 and 54.92, and the attributable proportion due to interaction was 41.53% and 75.59%, respectively.ConclusionsThe high level of BPDE-DNA adducts in blood is associated with HCC and that environmental exposure to B[a]P may increase the risk of HCC, especially among drinkers and populations with hepatitis B virus infection.     

The further development of a mammalian DNA alkaline unwinding bioassay with potential application to hazard identification for contaminants from environmental samples

Recently, we have detailed a DNA alkaline unwinding assay (DAUA) that can be used to rapidly measure chemically induced strand breaks in mammalian cells (Daniel et al., 1985). In this paper we present further development of this assay, including: (1) studies on the relationship between DNA adducts and DNA strand breaks; (2) evaluation of the role of cytotoxicity in DNA strand breaks; and (3) application of the DAUA to cell preparations from the liver of mice dosed with methylating agents. The level of DNA adducts produced in human CCRF-CEM cells by treatment with benzo(a)pyrene diol-epoxide (BPDE), N-acetoxy-2-acetyl aminofluorene (AAAF), and various methylating agents was linear with concentration over several orders of magnitude. Likewise, the level of strand breaks increased with the concentration over the same dose range. The strand breaks/adduct ratio ranged from 0.05 for the methyl adducts to 0.001 for the BPDE adducts. Using these values and the inherent sensitivity of the DAUA (circa 100 to 1000 breaks/cell), (Daniel et al., 1985), the ability of the assay to detect DNA damage induced by various classes of chemical carcinogens can be calculated. The DAUA appears to be useful for assessing the relative potency of various environmental genotoxic effects on mammalian cells. In addition, it can be conducted on cells isolated from target organs of whole animals.     

Intracellular calcium disturbances induced by arsenic and its methylated derivatives in relation to genomic damage and apoptosis induction

Arsenic and its methylated derivatives are contaminants of air, water, and food and are known as toxicants and carcinogens. Arsenic compounds are also being used as cancer chemotherapeutic agents. In humans, inorganic arsenic is metabolically methylated to mono-, di-, and trimethylated forms. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In recent years, the correlation between arsenic exposure, cytotoxicity and genotoxicity, mutagenicity, and tumor promotion has been established, as well as the association of arsenic exposure with perturbation of physiologic processes, generation of reactive oxygen species, DNA damage, and apoptosis induction. Trivalent forms of arsenic have been found to induce apoptosis in several cellular systems with involvement of membrane-bound cell death receptors, activation of caspases, release of calcium stores, and changes of the intracellular glutathione level. It is well known that calcium ion deregulation plays a critical role in apoptotic cell death. A calcium increase in the nuclei might lead to toxic effects in the cell. In this review, we highlight the relationship between induced disturbances of calcium homeostasis, genomic damage, and apoptotic cell death caused by arsenic and its organic derivatives.     

Risk assessment of environmental carcinogenesis using WBC DNA adducts

Environmental carcinogens are enzymatically activated to form intermediates that can react with cellular DNA and form DNA adducts. Several kind of carcinogens bind to several sites of DNA. The measurement of WBC DNA adducts is a useful indicator for environmental carcinogen exposure monitoring. The 32P-Postlabeling method is a most popular and very sensitive method for DNA adduct analysis. We can analyze 1 adduct/10(8) nucleotides. In this review, I show some data of DNA adduct analysis for PAH exposure. These results demonstrated that inter-individual variation was very large. There were some confounding factors, such as metabolism or repair variations. I also showed some limitations of DNA adduct analysis. The method of adduct analysis is very complicated with several steps. We need to improve the accuracy. Do the data from WBC explain the target organ, such as the lung or liver? Almost all previous studies have been cross-sectional. We need a large-sized cohort study to evaluate whether adducts are a predictor of cancer. DNA adducts should be an important factor in gene-environment interaction.     

Levels of DNA Adducts in the Blood and Follicular Fluid of Women Undergoing In Vitro Fertilization Treatment and Its Correlation with the Pregnancy Outcome

This study is designed to investigate the impact of DNA damage on pregnancy and fertilization rate outcome in a sub-sample of women undergoing IVF treatment. Blood and follicular fluid samples (n = 60) were analyzed for DNA adducts. While no BPDE-DNA adducts were detected, other unknown lipophilic adducts were seen in blood and follicular fluid. Women who failed to achieve pregnancy had higher DNA adducts in follicular fluid than those who succeeded (p < 0.05). Follicular fluid cotinine levels were associated with DNA adduct levels in blood and follicular fluid (p < 0.05). Evaluation of DNA damage resulting from oxidative stress could have a role in predicting IVF success rate.     

ERCC2/XPD单核苷酸多态与苯并芘体外诱导DNA加合物损伤的关联性研究

目的评价环境致癌因子苯并芘(B[a]P)所致DNA损伤修复与ERCC2/XPD单核苷酸多态(SNP)的关联。方法收集282例辽宁地区汉族健康人群外周血8ml,常规提取淋巴细胞及DNA,采用Taqman实时定量PCR检测ERCC2/XPDLys751Gln(rs13181),Asp312Asn(rs1799793)和Arg156Arg(rs238406)的基因型;体外培养淋巴细胞,应用B[a]P及S9活化系统,诱导BPDE-DNA加合物的形成;高效液相色谱法检测BPDE-DNA加合物含量;分析BPDE-DNA加合物水平与ERCC2/XPD SNP位点的关联。结果携带ERCC2/XPD Arg156Arg位点AA基因型个体BPDE-DNA加合物水平显著高于CC基因型携带者;50～70岁和≥70岁年龄组人群的加合物水平高于≤30岁年龄组(P<0.05);多元线性回归分析同样显示,ERCC2/XPD Arg156Arg位点SNP及年龄对BPDE-DNA加合物含量的影响有统计学意义(P<0.05)。结论 ERCC2/XPD Arg156Arg位点A等位基因可能与BPDE-DNA加合物的DNA修复能力降低相关联,可能会增加肿瘤易感风险。     

Biomarkers of individual susceptibility to carcinogens: Application for biological monitoring

In order to develop new markers of individual susceptibility to various human carcinogens, we studied some parameters of formation and metabolism of carcinogens, as well as DNA adducts formation and DNA repair in animals and humans. Following an i.p. administration of benzo(a)pyrene (BP) to the rats, levels of urinary excretion of BP-7,8-diol correlated with tumour latency. A high correlation was found between excretion of this metabolite and BP-DNA adducts level in the liver. Healthy smokers excreted higher quantities of BP-7,8-diol, than smoking lung cancer patients, thus confirming the suggestion on existence of cancer-prone phenotype. N-nitroso compounds formed most efficiently in stomach juice of children with superficial gastritis who therefore could be at high risk of stomach cancer. N-ethyl-N-nitro-N-nitrosoguanidine induced stomach cancer earlier in monkeys with a low level of DNA repair enzyme, O⁶-alkylguanine-DNA alkyltransferase (AGT) in gastric mucosa. Overall, these markers can be helpful in predicting individual susceptibility to carcinogens.     

多环芳烃宫内暴露DNA加合物的形成及相关基因多态性研究进展

生物标志能促进致癌物质易感性的评价,DNA加合物的形成在多环芳烃致癌过程中是关键的一步。由于多环芳烃在体内要经过代谢活化才能发挥致癌作用,因此不同的代谢酶及造成损伤后的修复过程都会影响到对PAHs遗传效应的评价。动物实验显示,发育中的胚胎可能对多环芳烃的遗传效应更敏感,多环芳烃的宫内暴露可能与多种不良出生结局有关。该文对多环芳烃宫内暴露母婴敏感性的差异、DNA加合物的形成及其与基因多态性之间的关系进行了综述。     

Esophageal cancer and microelements

Epidemiological studies have identified dietary zinc deficiency, methylbenzylnitrosamine, and ethanol as factors strongly associated with an increased incidence of esophageal carcinoma in man. In addition, these studies have identified other trace elements which may also affect the incidence of esophageal carcinoma. Animal models have confirmed that dietary zinc deficiency increases the incidence of methylbenzylnitrosamine-induced esophageal carcinoma and that dietary zinc deficiency also increases the incidence of other dialkylnitrosamine-induced carcinomas. The dialkylnitrosamine carcinogens are activated by NADPH-dependent cytochrome P-450 enzymes in their target tissues. The activated methylbenzylnitrosamine methylates DNA, forming O6-methylguanine adducts. These O6-methylguanine adducts can lead to point mutations in DNA, and such mutations are known to be responsible for the induction of certain carcinogen-induced tumors. We have demonstrated that dietary zinc deficiency increased the cytochrome P-450-dependent microsomal metabolism of methylbenzylnitrosamine and dimethylnitrosamine, two members of this class of dialkylnitrosamine carcinogens, while the addition of zinc in vitro noncompetitively inhibits the microsomal metabolism of these carcinogens. We have also demonstrated that dietary zinc deficiency is associated with an increased formation of O6-methylguanine in the esophageal DNA of zinc-deficient animals treated with methylbenzylnitrosamine. This increased formation of the mutagenic DNA adduct O6-methylguanine may explain the increased incidence of dialkylnitrosamine-induced carcinomas observed with dietary zinc deficiency. Other trace elements, including molybdenum, selenium, and magnesium, may also alter the incidence of esophageal carcinoma, but studies of these elements are not as conclusive as the epidemiological and experimental studies linking dietary zinc deficiency with an increased incidence of human esophageal carcinoma.     

Introduction

Epidemiological studies have identified dietary zinc deficiency, methylbenzylnitrosamine, and ethanol as factors strongly associated with an increased incidence of esophageal carcinoma in man. In addition, these studies have identified other trace elements which may also affect the incidence of esophageal carcinoma. Animal models have confirmed that dietary zinc deficiency increases the incidence of methylbenzylnitrosamine-induced esophageal carcinoma and that dietary zinc deficiency also increases the incidence of other dialkylnitrosamine-induced carcinomas. The dialkylnitrosamine carcinogens are activated by NADPH-dependent cytochrome P-450 enzymes in their target tissues. The activated methylbenzylnitrosamine methylates DNA, forming O6-methylguanine adducts. These O6-methylguanine adducts can lead to point mutations in DNA, and such mutations are known to be responsible for the induction of certain carcinogen-induced tumors. We have demonstrated that dietary zinc deficiency increased the cytochrome P-450-dependent microsomal metabolism of methylbenzylnitrosamine and dimethylnitrosamine, two members of this class of dialkylnitrosamine carcinogens, while the addition of zinc in vitro noncompetitively inhibits the microsomal metabolism of these carcinogens. We have also demonstrated that dietary zinc deficiency is associated with an increased formation of O6-methylguanine in the esophageal DNA of zinc-deficient animals treated with methylbenzylnitrosamine. This increased formation of the mutagenic DNA adduct O6-methylguanine may explain the increased incidence of dialkylnitrosamine-induced carcinomas observed with dietary zinc deficiency. Other trace elements, including molybdenum, selenium, and magnesium, may also alter the incidence of esophageal carcinoma, but studies of these elements are not as conclusive as the epidemiological and experimental studies linking dietary zinc deficiency with an increased incidence of human esophageal carcinoma.     

Environmental carcinogens and mutational pathways in atherosclerosis

Atherosclerosis is associated with DNA damage in both circulating and vessel-wall cells and DNA adducts derived from exposure to environmental mutagens are abundant in atherosclerotic vessels. Environmental chemical carcinogens identified as risk factor for atherosclerosis include polycyclic aromatic hydrocarbons (benzo(a)pyrene, dimethylbenz(a)anthracene, beta-naphthoflavone, pyrene, 3-methylcolanthrene), arsenic, cadmium, 1,3-butadiene, cigarette smoke. Accordingly, polymorphisms of genes encoding for phase I/II metabolic reaction and DNA repair are risk factor for cardiovascular diseases, although their role is negligible as compared to other risk factors. The pathogenic relevance of mutation-related molecular damage in atherosclerosis has been demonstrated in experimental animal models involving the exposure to chemical mutagens. The relevance of mutation-related events in worsening atherosclerosis prognosis has been demonstrated in human clinical studies mainly as referred to mitochondrial DNA damage. Atherosclerosis is characterized by the occurrence of high level of oxidative damage in blood vessel resulting from both endogenous and exogenous sources. Mitochondrial damage is a main endogenous source of oxidative stress whose accumulation causes activation of intrinsic apoptosis through BIRC2 inhibition and cell loss contributing to plaque development and instability. Environmental physical mutagens, including ionizing radiation, are a risk factor for atherosclerosis even at the low exposure dose occurring in case of occupational exposure or the high exposure doses occurring during radiotherapy. Conversely, the role of exciting UV radiation in atherosclerosis is still uncertain.This review summarizes the experimental and clinical evidence supporting the pathogenic role of mutation-related pathway in atherosclerosis examining the underlying molecular mechanisms.     

不同砷化合物对血管内皮细胞毒性的研究

目的观察不同砷化合物对体外培养的牛主动脉血管内皮细胞(BAEC)的细胞毒性。方法培养的BAEC分别暴露于亚砷酸钠(NaAsO2,iAsⅢ0~50μmol/L)、砷酸钠(Na2HAsO4,iAsⅤ,0~10mmol/L)和甲基亚胂酸(CH3AsO,MMAⅢ,0~2μmol/L)24h,应用四甲基偶氮唑盐(MTT)法测定细胞生存率;诱导性偶联质谱分光光度(ICP-MS)法测定细胞内总砷(tAs)含量。结果不同剂量范围内的iAsⅢi、AsⅤ和MMAⅢ均能够显著降低BAEC的细胞生存率(P<0.01),且具有剂量-效应关系;iAsⅢi、AsⅤ和MMAⅢ暴露24h的BAEC细胞的50%生存率(IC50)经计算分别为24.1μmol/L、155.9μmol/L和1.7μmol/L,对BAEC的细胞毒性从大到小依次为:MMAⅢ>iAsⅢ>iAsⅤ;相同暴露剂量和时间下,BAEC对MMAⅢ暴露的砷摄取速度明显高于iAsⅢ暴露(P<0.01)。结论无机砷甲基化的活性中间产物MMAⅢ对BAEC的细胞毒性要明显强于无机砷化合物。     

用AFLP结合免疫纳米磁珠技术富集分离BPDE-DNA片段

目的应用AFLP结合免疫纳米磁珠分离技术富集、分离与BPDE相互作用的DNA片段,从而为筛选BPDE致癌相关基因提供条件。方法应用AFLP技术和免疫纳米磁珠分离相结合技术获得差异片段,进行聚丙烯酰胺凝胶电泳及硝酸银染色观察。结果不同的选择性扩增引物组合均可得到清晰的多态性电泳图谱,以P1T2、P1T4、P1T3、P2T1、P3T4、P4T1、P5T2等组合扩增出的条带最多,均在60条左右,多态性丰富。对差异片段进行回收和PCR再扩增,再经琼脂糖凝胶电泳证实有回收产物出现,回收PCR再扩增片段与回收前的片段大小一致,成功富集、回收了差异片段。结论AFLP结合免疫磁珠分离技术可以分离富集BPDE-DNA片段,可作为筛选BPDE致癌相关的特异或易感基因的一种方法。     

Biotransformation and genotoxicity of fluoranthene in the deposit-feeding polychaete Capitella sp. I

Polycyclic aromatic hydrocarbons, such as fluoranthene (Flu), are of environmental concern because of their persistence, toxicity, and mutagenic properties. In this study we examined the genotoxicity of Flu to Capitella sp. I using the comet assay. We assessed patterns of DNA damage as a function of uptake route and as a function of exposure and depuration time and related levels of DNA damage to published information on Flu-metabolite formation. Exposure to approximately 30 microg Flu/g dry-weight sediment or 50 microg Flu/L seawater resulted in significant DNA damage. The degree of DNA damage was time dependent during both exposure and depuration, and although exposure route had no effect on the maximum degree of DNA damage occurring, it did influence the time course of damage. Levels of damage declined despite continued exposure to Flu, providing evidence for the induction of one or more DNA repair mechanisms. Comparison with Flu-metabolite profiles suggests that DNA damage is associated with the production of aqueous metabolites. The transitory nature of the DNA damage and repair process may contribute important insights into the mechanisms of toxicant effects at the molecular level but limits the usefulness of such endpoints as biomarkers of exposure or effect in ecotoxicological studies.     

Allium vegetables and organosulfur compounds: do they help prevent cancer?

Allium vegetables have been shown to have beneficial effects against several diseases, including cancer. Garlic, onions, leeks, and chives have been reported to protect against stomach and colorectal cancers, although evidence for a protective effect against cancer at other sites, including the breast, is still insufficient. The protective effect appears to be related to the presence of organosulfur compounds and mainly allyl derivatives, which inhibit carcinogenesis in the forestomach, esophagus, colon, mammary gland, and lung of experimental animals. The exact mechanisms of the cancer-preventive effects are not clear, although several hypotheses have been proposed. Organosulfur compounds modulate the activity of several metabolizing enzymes that activate (cytochrome P450s) or detoxify (glutathione S-transferases) carcinogens and inhibit the formation of DNA adducts in several target tissues. Antiproliferative activity has been described in several tumor cell lines, which is possibly mediated by induction of apoptosis and alterations of the cell cycle. Allium vegetables and organosulfur compounds are thus possible cancer-preventive agents. Clinical trials will be required to define the effective dose that has no toxicity in humans.     

Bulky DNA adducts, 4-aminobiphenyl-haemoglobin adducts and diet in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study

In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0.02), vitamin E (P = 0.04) and alcohol (P = 0.03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P = 0.03, 0.04, and 0.03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances.     

硒和砷对HepG2细胞氧化应激和DNA氧化损伤及修复的作用

目的研究硒和砷单独及联合作用对HepG2细胞氧化应激和DNA氧化损伤及修复的影响。方法采用不同浓度的硒(2.5、5.0和10.0μmol/L亚硒酸钠)和砷(1.56、3.13、6.25、12.5和25.0μmol/L亚砷酸)为受试物单独或联合处理HepG2细胞。荧光法测定丙二醛(MDA)作为氧化应激的指标,高效液相色谱-电化学检测法(HPLC-EC)测定8-羟基鸟苷(8-OHdG)作为DNA氧化损伤的指标,Western Blot检测hOGG1表达作为DNA氧化损伤修复的指标。结果在硒和砷单独作用的条件下,可观察到:(1)5.0、10.0μmol/L的亚硒酸钠和6.25、12.5、25.0μmol/L的亚砷酸均引起HepG2细胞MDA含量增加、8-OHdG生成增多、hOGG1表达明显下降(P<0.05,P<0.01);(2)较低浓度的亚硒酸钠(2.5μmol/L)具有有限的抑制8-OHdG生成的作用(P>0.05)。在硒和砷联合作用的条件下,可观察到:(1)2.5μmol/L的亚硒酸钠和6.25μmol/L的亚砷酸同时染毒使MDA含量和8-OHdG的生成均较相应砷剂量组下降(P<0.05);(2)2.5μmol/L的亚硒酸钠与6.25、12.5和25.0μmol/L的亚砷酸同时染毒,hOGG1表达与相应砷剂量组比较没有明显差异(P>0.05)。结论5.0、10.0μmol/L的亚硒酸钠和6.25、12.5、25.0μmol/L的亚砷酸均可引起HepG2细胞氧化应激增强、8-OHdG生成增多、hOGG1表达明显下降;一定剂量的硒(2.5μmol/L的亚硒酸钠)对砷诱导的HepG2细胞氧化应激和DNA氧化损伤具有抑制作用,但对砷所致的DNA氧化损伤修复不产生明显影响。     

环境致癌剂与p53基因突变

p5 3基因是至今为止发现的与人类肿瘤相关性最高的基因。它不仅作为抑癌基因发挥作用 ,还参与细胞周期调控、DNA损伤与修复、基因转录及细胞凋亡等多个过程。肿瘤病因学的研究表明 ,6 0 %～ 90 %的人类肿瘤是由环境中的化学致癌物引起。环境中的化学致癌物或前致癌物可以造成p5 3基因突变及蛋白表达的改变 ,且p5 3的突变形式也随着致癌物和肿瘤的类型不同而具有特征性的差异 ,相关研究已成为近年来肿瘤分子生物学的热点。本文综述了苯并 [a]芘、烟草、亚硝胺、黄曲霉毒素和氯乙烯等几种环境中存在的主要化学致癌物质的致癌效应以及对p5 3基因和P5 3蛋白的影响。