Studies on N-nitroso bile acid amides in relation to their possible role in gastrointestinal cancer.
Cancers of the gastrointestinal tract account for a large proportion of neoplastic diseases which afflict humans. The etiology of gastrointestinal cancer has been attributed in part to exogenous carcinogens, such as food substances and environmental pollutants. Recent hypotheses suggest that carcinogens may arise endogenously. Evidence suggests that some bile acids and their isomeric metabolites may be involved in the pathogenesis of colon cancer. However, the mechanisms responsible for their cancer-promoting effect is not clear. We and others propose that one mechanism for the mitogenic effects of bile acids may be N-nitrosation of their glycine and taurine amides; human gastric aspirates do contain small quantities of N-nitroso compounds of other substrates. Many foods contain nitrites and nitrates, which can react with bile acid amides to form N-nitroso derivatives. Our recent studies demonstrated the potential for N-nitroso conjugate formation from ursodeoxycholic acid, a 7 beta-epimer of chenodeoxycholic acid used as a drug Actigall to dissolve gallstones. The N-nitroso derivative of this compound, a direct-acting carcinogen, has a long half-life and, once nitrosated is stable enough to survive passage through the gastrointestinal tract. We describe the synthesis of N-nitrosated derivatives of various bile acid conjugates and mechanisms of decomposition of (Z)- and (E)-bile acid diazoates. Studies of the effects of enzymes such as cholylglycine hydrolase on the N-nitroso bile acid conjugates and their reaction with DNA are also described. These studies may have important implications in the interplay of diet with endogenous substrates in the etiology of cancers of the stomach, liver, and colon.
Dayal
B
B
Department of Medicine, New Jersey Health Care System, V.A. Medical Center, East Orange 07018, USA. dayalbi@umdnj.edu
Ertel
N H
NH
D000581:Amidohydrolases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism*; D002793:Cholic Acids / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000209:etiology*; D006801:Humans; D013058:Mass Spectrometry; D015394:Molecular Structure; D009153:Mutagens; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009603:Nitroso Compounds / Q000737:chemistry* / Q000378:metabolism*
D001647:Bile Acids and Salts; D002273:Carcinogens; D002793:Cholic Acids; D009153:Mutagens; D009566:Nitrates; D009573:Nitrites; D009603:Nitroso Compounds; D004247:DNA; D000581:Amidohydrolases; C023154:choloylglycine hydrolase