4-Hydroxy-1-(3-pyridyl)-1-butanone, an indicator for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA damage, is not detected in human pancreatic tissue.

Tobacco smoking is the only known etiologic agent that causes pancreatic cancer. The tobacco-specific nitrosamine 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in laboratory rodents that, independent of the route of administration, induces primarily lung adenocarcinoma (1). When administered in drinking water, NNK and its metabolite 4-(methy1nitrosamino)-1(3-pyridy1)-1-butanol (NNAL) also induce cancer of the pancreas in rats (2). NNK and NNAL are present in human pancreatic juice (3). Human pancreatic tissue is capable of metabolizing NNK to NNAL, keto acid [4-oxo4-(3-pyridyl)-1-butanoic acid], and keto alcohol [4-hydroxy1-(3-pyridyl)-1-butanone (HPB); ref. 4]. These metabolic pathways lead to formation of electrophiles that readily react with cellular macromolecules including DNA. Tobacco-specific nitrosamine–induced DNA adducts identified include O-methylguanine, 7-methylguanine, and 4-methylthymidine. There are also NNK adducts resulting from pyridyloxobutylation of DNA, such as O-[4-oxo4-(3-pyridyl)but-l-yl]guanine, 7-[4-oxo-4-(3-pyridyl) but-1-yl]guanine, N-[4-oxo-4-(3-pyridyl)but-1-yl]guanine, O-[4-oxo-4-(3-pyridyl)but-1-yl]cytidine, and O-[4-oxo-4(3-pyridyl)but-1-y1)thymidine (ref. 5 and references therein). Tobacco smoke induces oxidative stress; oxidative damage markers in biological specimens of smokers were detected at levels significantly higher than those in nonsmokers (reviewed in ref. 1). NNK has also induced oxidative damage in rodent lungs as illustrated by elevated levels of 8-hydroxy-2V-deoxyguanosine (8-OHdG) (6). We hypothesized that the presence of NNK in human pancreatic juice may result in the formation of 8-OHdG and HPB-releasing DNA adducts derived from the pyridyloxobutylation pathway in pancreatic tissue; such DNA damage is prerequisite, but not sufficient, for the initiation of carcinogenesis in this organ. Materials and Methods