Early biochemical markers of effects: enzyme induction, oncogene activation and markers of oxidative damage.
Experimental carcinogenicity studies focus on identification of single carcinogens. Humans, however, appear exposed to a variety of low doses of carcinogens. Furthermore, few chemical entities are carcinogenic or toxic per se, but require metabolic activation to form ultimate carcinogens or toxins. In contrast to experimental animals, humans show considerable difference in genetic properties. In that situation it is particularly important to estimate individual capability for metabolic activation. To an increasing extent, activation includes formation of toxic oxygen metabolites. Particular targets for activated species are DNA and lipids; in particular low-density lipoproteins (LDL). Modifications of DNA are important for initiating the multistep process of carcinogenesis, in particular if oncogenes are activated or if tumor supressor genes are inactivated. Such DNA modification can be identical regardless of the reactive specimens being a xenobiotic or an oxygen species. Modification of LDL can start the process of atherosclerosis by transforming macrophages into foam cells, deposited as fatty streaks in the arterial wall. Biomarkers for activation capacity of xenobiotics include the use of prototype substrates and molecular techniques to determine genetic polymorphisms. Oxidative DNA modification can be measured from urinary excretion of oxidatively modified deoxynucleosides, particularly guanosine. Future efforts have to include individual measurements in order to improve the 'resolution' of molecular epidemiological approaches.
Poulsen
H E
HE
Department of Pharmacology, Health Science Faculty, Panum Institute, Copenhagen, Denmark.
Loft
S
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D015415:Biomarkers; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D003580:Cytochromes / Q000096:biosynthesis / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004790:Enzyme Induction; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D009857:Oncogenes; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism
D015415:Biomarkers; D002273:Carcinogens; D003580:Cytochromes; D008077:Lipoproteins, LDL; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D010100:Oxygen