Carcinogenic aromatic amine metabolism and DNA adduct detection in humans.
Human exposure to carcinogenic aromatic amines can occur from a variety of sources, including cigarette smoke and cooked foods. Initial metabolism occurs primarily in the liver and involves N-hydroxylation by cytochrome P-450IA2 and N-acetylation by acetyltransferase, which serve as competing activation and detoxification reactions, respectively. Both enzymes are polymorphic in humans and individual phenotype can be readily assessed using caffeine ingested in coffee followed by urinary metabolite analysis. N-hydroxy arylamines can then be transported through the blood where they can form protein adducts with hemoglobin or undergo renal filtration into the urinary bladder lumen where, at acidic pH, they can react covalently with urothelial DNA. Carcinogen-DNA adduct levels in human bladder are smoking-related and the C8-deoxyguanosine derivative of 4-amino-biphenyl (ABP) is a major product. Alternatively, N-hydroxy arylamines can be conjugated in the liver by glucuronyl transferases which provides a mechanism for biliary transport to the colon lumen where beta-glucuronidases can regenerate the aglycone. In the colon mucosa, acetyltransferases can further activate the N-hydroxy metabolite by O-acetylation; and persons with the rapid acetylation phenotype are known to be at higher risk for colorectal cancer. Detection of specific arylamine-DNA adducts in human colon should provide direct evidence for the role of these carcinogens in the etiology of this disease.
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National Center for Toxicological Research (HFT-100), Jefferson, Arkansas 72079.
D000123:Acetyltransferases / Q000502:physiology; D000588:Amines / Q000009:adverse effects / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000139:chemically induced; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
D000588:Amines; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000123:Acetyltransferases