Prediction and monitoring of the carcinogenicity of polycyclic aromatic compounds (PACs).
Chemical carcinogenesis is a multistage process that includes initiation, promotion, and progression. Some carcinogenic PACs have been shown to activate proto-oncogenes and deactivate tumor-suppression genes in the carcinogenic process. The function of DNA repair processes appears to be changed in some cases by PACs. Many PACs are well known for their carcinogenic activity, but for this activity to be exerted, metabolic activation by microsomal enzymes must occur. The enzyme system responsible for PAC activation is the mixed-function oxidase system and, in particular, cytochrome P-450. In the case of PAHs, oxidation predominantly produces reactive diol-epoxides that can then be converted to carbonium ions as the reactive electrophiles that can then covalently bind to DNA. Regions of high activity exist in PAHs, namely, the "bay," "K," and "L" regions which are associated with pi electron distribution. The diol-epoxides can exist in either syn or anti forms, each of which has two enantiomers producing four stereoisomers in all. Energy considerations favor the formation of the anti form. Nitrogen-containing PACs can be metabolically activated in a manner similar to that for PAHs, or the nitrogen atom can be oxidized to form hydroxylamines. These reactive electrophiles can then form covalently bound DNA adducts. The monitoring of DNA adducts has been used in risk assessment for human exposure to PACs. This form of biomonitoring has advantages over the monitoring of external exposure or body levels of the chemicals in question. In the case of PACs, binding to DNA is an important step in the multistage carcinogenic process. The estimation of DNA adducts has been used in the monitoring of humans exposed to PAHs in a wide range of industrial situations. Recent research has shown a dose-response relationship between PAH adduct levels and human cancer, thus developing molecular epidemiology as a relevant science for the field of risk assessment. Techniques have been developed for the determination of DNA adducts and these include immunochemical, fluorescence spectroscopic, GC-MS, and 32P-postlabeling methods. The 32P-postlabeling assay is by far the most sensitive, with limits of detection being of the order of one adduct in 10(10) normal nucleotides. The use of HPLC for separation of adducted nucleotides in this postlabeling assay is becoming more common and gives better resolution of adducts than does the TLC technique used in the traditional assay. The detection of adducts on hemoglobin and other proteins has been used as a surrogate for DNA adduct estimation.(ABSTRACT TRUNCATED AT 400 WORDS)
Shaw
G R
GR
National Research Centre for Environmental Toxicology, Queensland, Australia.
Connell
D W
DW
D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004784:Environmental Monitoring; D006801:Humans; D011083:Polycyclic Compounds / Q000009:adverse effects*; D013329:Structure-Activity Relationship
D002274:Carcinogens, Environmental; D011083:Polycyclic Compounds