TOBACCO-SPECIFIC NITROSAMINE ADDUCTS - STUDIES IN LABORATORY-ANIMALS AND HUMANS

This paper describes quantitation of human hemoglobin and DNA adducts of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino )-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). NNK and NNN are believed to be involved in cancers of the lung, esophagus, oral cavity, and pancreas in people who use tobacco products. The add uct dosimetry method employs GC-MS for quantitation of 4-hydroxy-1-(3- pyridyl)-1-butanone (HPB) released by mild base hydrolysis of hemoglob in or acid hydrolysis of DNA as a biochemical marker of the pyridyloxo butylation metabolic activation pathway. Approximately 22% of smokers (n = 101) had elevated levels of HPB released from hemoglobin (range, 200-1600 fmole/g Hb). Adduct levels in snuff dippers ranged from 200-1 800 fmole/g Hb. HPB levels in nonsmokers were generally below the dete ction limit. Acid hydrolysis of lung and tracheal DNA obtained at auto psy and analysis for released HPB revealed levels ranging up to 50 fmo le/mg DNA in smokers; the adduct was not detected in nonsmokers. These findings are consistent with data generated in studies of adduct form ation by NNK in rats. The biological significance of the HPB-releasing DNA pyridyloxobutylation pathway was compared to that of the DNA meth ylation pathway in the A/J mouse. These studies demonstrated that the persistence of O6-methylguanine in lung DNA is critical for tumorigene sis by NNK and that pyridyloxobutylation enhances both persistence of O6-methylguanine and tumorigenesis by acetoxymethylmethylnitrosamine. In the rat, the relative roles of methylation and pyridyloxobutylation in lung tumorigenesis by NNK are not as clearly defined. Although the biological significance of DNA methylation in NNK tumorigenesis is we ll characterized, dosimetry studies of tobacco-specific nitrosamines i n humans should be carried out using biochemical markers of the pyridy loxobutylation pathway because of their specificity to tobacco product s.