The role of DNA adducts in chemical carcinogenesis.

The reaction of chemical carcinogens with DNA appears to be one of the earliest events in the initiation phase of cancer. These DNA reactions can be base- and position-specific, are affected by sequence context, and are repaired at different rates depending on whether or not they are on the transcribed or nontranscribed strand of DNA and which nucleotide sequence is modified. Thus, measurement of total genomic DNA reaction of carcinogens is only a crude first step in dissecting out which are the critical lesions for cancer initiation. On the other hand, we know that DNA adducts, which have been primarily characterised in experimental studies, appear to have similar structures in human DNA arising from occupational or environmental exposures. A number of different methods have been developed to detect and measure DNA adducts in man. These include physico-chemical methods such as mass spectrometry, 32P-postlabelling, fluorescence and accelerator mass spectrometry (AMS) and biological methods such as immunoassay. All these methods have their strengths and weaknesses. Human studies, using 32P-postlabelling, demonstrate that this method can be used to examine the effect of potential chemoprotective agents on DNA adduct level. AMS has been used to measure DNA adducts in human tissue after patients have ingested trace quantities of the food mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a heterocyclic amine formed during the cooking of meat and the naturally occurring mycotoxin, aflatoxin B1. These studies can assist in assessing the risks associated with low-level exposure to food genotoxins.