ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The human body is endowed with a large number of xenobiotic chemical metabolizing enzymes, a significant proportion of which are polymorphic and thus render one individual at greater or lesser risk than another of chemically-induced disease. All examples of genetic polymorphism of chemical metabolizing enzymes have been reviewed in relation to their potential to activate and detoxicate procarcinogens and promutagens. Many examples are cited whereby phenotype can act as a carcinogenic risk factor. With the availability of a large amount of DNA sequence data for chemical metabolizing enzymes there has emerged a number of polymerase chain reaction (PCR) strategies aimed at discerning one metabolic phenotype or another. This is seen as a very positive and democratic scientific development, widening the franchise for studies of disease risk. Nevertheless, it is argued that, at these early stages with many laboratory-based scientists scarcely familiar with epidemiological study design, a cautious approach should obtain when interpreting single studies.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Three polymorphic cytochrome P450 genes that have attracted interest for their potential role in human pulmonary carcinogenesis, i.e.CYP1A1,CYP2D6andCYP2E1, were studied in a population consisting of 106 lung cancer patients and 122 healthy controls. Polymorphism of theCYP2D6gene encoding for debrisoquine hydroxylase was determined using Xba I restriction fragment length polymorphism (RFLP) analysis together with a PCR based method. All of the three most common presently known defective alleles ofCYP2D6were detected by this application. Subjects having genotypes either homozygous or heterozygous for theCYP2D6wild type alleles were classified as extensive metabolizers (EMs) of debrisoquine whereas poor metabolizers (PMs) had two defective allales. The PM individuals are thought to be less prone to develop lung cancer. TheCYP1A1andCYP2E1genes were studied by RFLP analyses usingMspI andDraI restriction enzymes, respectively, giving rise to two different sized hybridizable fragments in Southern blot analyses. In these RFPL analyses genotypes homozygous to the mutated allele have been presented as potent determinants of individual lung cancer risk. In the present study no association between polymorphicCYP1A1andCYP2E1genotypes and susceptibility to lung cancer was found. However,CYP2D6polymorphism studies of the 122 healthy controls revealed seven poor metabolizer genotypes (5.7%), which compares well with the previously observed phenotypic distribution in the Finnish population, whereas only one PM genotype (1/106) was found among the lung cancer patients. These results agree with the previous suggestions that PMs of debrisoquine are less susceptible to lung cancer than EMs.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The cytochromes P450 participate in the metabolic activation of precarcinogens. Recent results reveal that many P450 genes are polymorphically distributed. Different investigators have tried to link polymorphic variants of theCYP1A1,CYP2D6andCYP2E1genes to the incidence of cancer, particularly lung cancer, in Asian and Caucasian populations. In the current overview we briefly summarize this research. It appears that interesting functionally linked interindividual differences in theCYP1A1gene have been found and could be of importance in understanding differences in susceptibility to lung cancer. On the other hand, the data presented regardingCYP2D6andCYP2E1are less promising. We also describe interethnic differences in the P450 gene structures as a major obstacle for extrapolation of results between different ethnic groups.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Humans are exposed to preformed N-nitroso compounds (NOC)‡, but also to a wide range of precursors and nitrosating agents which can react in vivo to form potentially carcinogenic NOC and diazo compounds. Nitrite, nitrate and nitrosating agents can also be synthesized endogenously in enzymic reactions mediated by bacteria, activated macrophages and neutrophils. The latter two cell types generate, via the enzyme nitric oxide synthase, the nitric oxide radical that is involved in cytotoxicity, and is believed to be involved in formation of carcinogenic nitrosamines, DNA base deamination and oxidative damage. Thus endogenous NOC formation, DNA damage and gene mutations in humans could occur at various sites of the body such as the stomach and chronically infected or inflamed organs. Sensitive procedures to estimate the exposure of humans to NOC have been developed and applied in ecological and cross-sectional studies. These have shown that inhabitants of high-risk areas for stomach and esophageal cancer, patients with urinary tract infections (at risk for bladder cancer) and Thai subjects infected with liver fluke (at risk for cholangiocarcinoma) had significantly higher exposure to endogenous NOC. Clinical studies have examined the model of stomach carcinogenesis based on intragastric nitrosation, but the precise roles of bacterial overgrowth and ofHelicobacter pyloriinfection in NOC synthesis and/or inducing oxidative stress in stomach mucosa remain to be clarified.Together these results support the role of NOC and other nitrite-derived mutagens in human cancer etiology, in particular when exposure starts early in life and persists over a long period. In various human tumours, C to T transition mutations have been frequently detected in the tumour-suppressor gene p53. Whether this type of mutation is mediated by nitric oxide synthase (viadeamination of 5-methyIcytosine to T at CpG islands) is now being examined in molecular pathology and epidemiological studies.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Various epidemiological studies have given evidence on the correlation between alcohol intake and different types of cancer, especially in the upper alimentary and respiratory tract and in the liver. This review discusses the tumour stimulating effects of ethanol associated mechanisms.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Products of incomplete combustion are identified as a major source of carcinogenic risk in urban areas, especially those from small non-industrial sources. The major ubiquitous emission sources outdoors in populated areas are residential home heating and motor vehicles. Indoors the major combustion source is environmental tobacco smoke. Polycyclic organic matter adsorbed onto the particles emitted from incomplete combustion are estimated to make the largest contribution to human genotoxic and cancer risk. Mutagenic emission factors combined with dispersion modelling indicated that automobiles and heating sources were major sources of mutagens. Ambient air studies to apportion the sources of mutagens in non-industrial areas confirmed this prediction. To apportion and estimate the cancer risk of ambient organic matter from particles invivoanimal tumour data, receptor modelling and human exposure data were combined. Tumourigenicity studies of the source apportioned ambient organic matter provided the relative tumour potencies of two ambient samples of different source composition. The human cancer unit risks were developed based on the comparative potency method using tumour data from these ambient samples. Residential wood combustion accounted for 75% of the exposure to particle associated organics, but only 20% of the estimated cancer risk. The remaining 80% of the risk appears to be associated with the mobile source component and atmospheric transformation products from these source emissions.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Urban air pollution, originating in western countries mainly from automotive engine exhausts, contains thousands of components, many of which are genotoxic, i.e. are putative cancer initiators. Other pollution components, such as NO2and certain particles, may have cocarcinogenic/promotive effects, at least at higher exposure levels. Cancer risk assessment of this complex mixture has to combine data from the exposure history, from epidemiological studies as well as from animal carcinogenicity tests, and from in vitro studies of fractions and individual components. Data for metabolism and pharmaco-kinetics have also to be considered. A multiplicative linear model is assumed to be valid for cancer initiation at low levels. Attempts are being made to determine the target dose from ultimate carcinogens (reactive metabolites)viamacromolecule adduct levels, and to base the risk assessment on the radiation-dose equivalent to the chemical dose. So far this has been possible only for simple alkenes, which are metabolized to epoxides, and indirectly, via benzo(a)pyrene (BaP), for particle-bound polycyclic aromatic hydrocarbons (PAH). The lifetime risk of cancer (all sites) from ethene is estimated accordingly to 1.4 x 10-4per fig µg m-3, and from PAH to 12 x 10-4per ng m-3BaP. For other components indicated to give risk contribution (NOx, volatile PAH, benzene, aldehydes, butadiene) essential data are lacking and only very rough estimates can be given at this time.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Coke oven workers are exposed to high concentrations of polycyclic aromatic hydrocarbons. Only recently have methods been developed to try to assess the individual, biologically significant exposure. The only coke oven plant in Finland started to function in 1987, in Raahe, enabling the implementation of a cohort study among the workers to determine the usefulness of some currently available biomonitoring methods, e.g. methods of measuring PAH-DNA adducts. Urine and blood samples were taken several times from a sample of workers starting from before they worked at the plant. A questionnaire (smoking, diet, former and current occupations) was filled in by the workers at every sampling, and air samples (personal and stationary) were collected at the same time. The mean values of both benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were measured by synchronous fluorescence spectrophotometry (SFS) and the antibodies to these adducts increased somewhat after the work at the plant started. However, all the adduct values were low, and no differences between the smokers and non-smokers at any time point were detected. Battery workers had slightly increased means of BPDE-DNA adducts compared to non-battery workers. Also, coke oven workers had slightly higher adduct values than age, sex and smoking matched controls.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We have examined breast tumour samples from 109 unselected breast cancer patients for genetic changes on chromosomes 13 and 17. We have looked for allelic losses, firstly, at the retinoblastoma locus, RB1, on chromosome 13q, and secondly, on both arms of chromosome 17. We have also studied the same samples for amplification of theerbB2oncogene. We searched for mutations in four well conserved areas of thep53gene using constant denaturant gradient electrophoresis (CDGE). Allelic loss or rearrangement was detected in a large proportion of the tumours, affecting 37-51% of cases with different probes. The areas most frequently affected were 17pl3.1 and 17pl3.3. Point mutations and small deletions in thep53gene on 17pl3.1 were detected in 16% of the tumours. The data on genetic changes were then analyzed for three different correlations: 1) co-operation between different lesions, 2) association with family history of breast cancer, 3) correlation with clinical factors and prognosis. There was association between losses at the retinoblastoma locus and losses on 17p and 17q. We also found an association betweenp53mutations and amplification of theerbB2oncogene. Relatives of patients having deletions at the retinoblastoma locus and/or sites on chromosome 17 in the tumours have a significantly increased relative risk of developing breast cancer. No such correlation is found forp53mutations orerbB2amplification. Nop53germline mutations were detected.P53mutations do, however, appear to be a strong indication of poor prognosis in this population.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID