ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Molecular approaches have attained a central position in modern experimental and human toxicology by providing the means to study basic underlying mechanisms. Molecular methods can be used to identify causal associations that would otherwise be obscure and to make better quantitative estimates of those associations at relevant levels of exposure. They may also make it possible to identify susceptible groups or individuals who are at risk of suffering the toxic effects of certain types of environmental and occupational agents. The use of transgenic animals in toxicology will improve our understanding of the role of toxic chemicals, such as carcinogens and mutagens, and their dosimetry and target organs. The use of molecular approaches in toxicology should thus result in better estimates of risks to human health.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Expression of enzymes metabolizing drugs, carcinogens, and other chemicals (“xenobiotics”) is regulated by the interplay of genetic, host, and environmental factors, leading in human populations to a marked interindividual variability. On this basis it is speculated that individual differences in cancer susceptibility could be explained to a certain extent by interindividual differences in metabolic activation. CYP dependence of carcinogen activation is briefly reviewed; CYP2A6 as a more specific example and some consequences and corollaries are briefly discussed. At present, no consensus has been reached about the significance of interindividual differences (genetic or nongenetic) in carcinogen metabolism in cancer etiology. The likely reason is that chemically induced cancer is still a multifactorial, multistage disease involving numerous events before a clinically manifested disease develops. Molecular biological methods such as RFLP and PCR-based techniques as well as molecular dosimetry are making it possible to investigate the genetic background of individual subjects and environmental influences without biases caused by diseases, age, treatment, and other factors, which have plagued studies thus far.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

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 CYP 1A1, 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.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Individual susceptibility to lung cancer due to occupational and environmental exposures to carcinogenic agents has been shown to be modulated by host-specific factors. The underlying principle of these factors is the differences that confer sensitivity or resistance to the disease. Since the majority of chemical carcinogens are not capable of causing hazardous effects per se, the metabolism of these compounds is a crucial part of the initial host response to the environmental exposure. Disturbances in the balance between activation and detoxification may thus explain the individual variations in responses to exposures to carcinogens. Many of the metabolic enzymes have recently been shown to express genetic polymorphisms in the population, and an association has been found between cigarette smoke-induced lung cancer and CYP1A1, CYP2D6, and GSTM1 genes. In addition, GSTM1 and NAT2 polymorphisms have been associated with susceptibility to bladder cancer. Since substantial ethnic differences exist in the distribution of altered and normal alleles, and findings in one ethnic group are not necessarily applicable to others, these biomarkers are still in the validation stage. However, as more information emerges on the specific features that lead to enhanced susceptibility they can undoubtedly be used to determine risks of environmental exposures to susceptible individuals and populations.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Application of methods to the measurement of DNA adducts in occupational and environmental studies was surveyed. The methods included the32P-postlabeling assay, immunoassay, mass spectrometry, and synchronous fluorescence spectroscopy. Methods for detecting excreted urinary RNA and DNA adducts were also discussed. When the techniques have been applied in occupational settings with complex exposures, identification and quantitation of the adduct levels have not been possible. At present emphasis is being placed on the determination of specific adduct levels. This can often be achieved by adding a purification step before the determination of adducts. Inasmuch as humans differ in their metabolic capacity, it has become feasible to determine adducts in humans who are polymorphic in their xenobiotic metabolism.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Polycyclic aromatic hydrocarbon carcinogens are usually activated for DNA binding by the metabolic formation of bay region dihydrodiol epoxides with R,S,S,R stereochemistry. Such metabolites from planar hydrocarbons reacted preferentially with the amino groups of deoxyguanosine residues, whereas those from nonplanar hydrocarbons were more efficiently trapped by DNA and reacted preferentially with the amino groups of deoxyadenosine residues, in some cases. Molecular modeling and NMR measurements indicated that the conformations of DNA adducts depend upon the hydrocarbon involved and the cis or trans opening of the epoxide ring during adduct formation. The structural characterization of carcinogen- DNA adducts and investigations of relationships between specific adducts and biological effects represent an important background that can be valuable in molecular epidemiological approaches.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Point mutations in the p53 tumor suppressor gene are the most common genetic alterations in human cancers. The nature and location of these mutations can be informative in assessing the importance of putative carcinogenic agents. Potential associations between a given carcinogen and a specific mutation pattern can be substantiated when the exposure history of the patients is known. While the past exposure to environmental risk factors is often difficult to determine, documented occupational exposure to carcinogens presents a unique situation for evaluating this approach. Analysis usually involves working with paraffin-embedded tissues, fixed under conditions suboptimal for genetic analysis and stored for many years, since frozen tissues are not available in sufficient numbers. The particular methodological problems encountered with fixed samples are discussed here, using as illustration an ongoing study of oncogene and tumor suppressor gene mutations in archived bladder tumors of workers exposed to aromatic amines and nonexposed patients.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This paper reviews mutational activation of ras oncogenes and inactivation of the p53 tumor suppressor gene in human lung cancer. We discuss the frequency, type, and location of mutations in these genes in relation to known etiological factors for lung cancer. The most studied examples of these are exposure to tobacco smoke, and to radon and asbestos fibers at work. We summarize data from our laboratory on K-ras and p53 mutations in fresh tissue samples from patients with resected primary lung carcinoma whose smoking and occupational histories were known. Most of the tumors examined were histologically non-small cell carcinoma (NSCLC), mainly of the squamous cell carcinoma and adenocarcinoma types. We compare the prevalence and nature of mutations in the two histological types of NSCLC.

ISSN:1076-2752    

出版商:OVID    

年代:1995

数据来源: OVID