Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis.
The metabolic pathways associated with carcinogenic aromatic amines in humans provide an excellent example of polymorphisms that appear to be relevant to human carcinogenesis. In this regard, the N-acetylation of arylamines and the O-acetylation of their N-hydroxy metabolites are catalyzed preferentially by a genetically polymorphic acetyltransferase, high activity of which has been correlated with decreased risk for urinary bladder cancer and increased susceptibility to colorectal cancer. Cytochrome P450IA2, the principal liver enzyme involved in aromatic amine N-oxidation, exhibits a wide interindividual variation that appears trimodal in several populations and is clearly inducible by cigarette smoking and probably other host factors as well. UDP-Glucuronosyltransferases, which catalyze the N-glucuronidation of N-hydroxyarylamines and are likely to be responsible for their transport to the colon, show widely varied but unimodal distributions in humans. In contrast, human liver sulfotransferase activity for N-hydroxyarylamines, which would be expected to decrease their transport through the circulation, is catalyzed by a polymorphic enzyme(s) that is expressed at higher levels in blacks, as compared to whites, and could contribute to their relatively lower incidence of urinary bladder cancer. Peroxidative activation of aromatic amines can also occur, especially from prostaglandin H synthase in the urinary bladder and myeloperoxidase in the lungs of cigarette smokers, and both show considerable individual variability, apparently due to the extent of tissue inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Kadlubar
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Office of Research (HFT-100), National Center for Toxicological Research, Jefferson, AR 72079.
Butler
M A
MA
Kaderlik
K R
KR
Chou
H C
HC
Lang
N P
NP
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000588:Amines / Q000378:metabolism*; D003106:Colon / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000209:etiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D010544:Peroxidases / Q000378:metabolism*; D010641:Phenotype; D010865:Pilot Projects; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000209:etiology
D000588:Amines; D003577:Cytochrome P-450 Enzyme System; D010544:Peroxidases; D000123:Acetyltransferases; D014453:Glucuronosyltransferase; D015238:Sulfotransferases