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Functional effects of human N‐acetyltransferase‐2 (NAT2) single nucleotide polymorphisms (SNPs) on the activation of arylamine carcinogens
Author(s) -
Doll Mark A,
Hein David W.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a414-c
Subject(s) - carcinogen , n acetyltransferase , chemistry , single nucleotide polymorphism , acetyltransferase , hydroxylation , cytochrome p450 , heterocyclic amine , biochemistry , arylamine n acetyltransferase , acetylation , metabolism , enzyme , genotype , gene
Humans are exposed to dietary carcinogens 2‐amino‐3‐methylimidazo [4, 5‐f] quinoxaline (IQ), 2‐amino‐1‐methyl‐6‐phenylimidazo [4, 5‐b]‐pyridine (PhIP) from well‐done cooked meats and to an environmental carcinogen 4‐aminobiphenyl (ABP) from cigarette smoke. Bioactivation of these compounds includes cytochrome P450‐catalyzed N‐hydroxylation followed by O‐acetylation catalyzed by N‐acetyltransferase‐2 (NAT2). To investigate the functional consequences of SNPs in the NAT2 coding region on metabolic activation via O‐acetylation, reference NAT2 *4 and NAT2 variant alleles possessing one of eleven SNPs in the NAT2 coding region were cloned and expressed in yeast (Schizosaccharomyces pompe). Metabolic activation of N‐OH‐PhIP, N‐OH‐IQ and N‐OH‐ABP were determined by measuring dG‐C8‐PhIP, dG‐C8‐IQ and dG‐C8‐ABP adducts that form spontaneously from the acetoxy metabolites. SNPs 111T>C, 282C>T, 481C>T, 759C>T, and 803A>G (K268R) had no significant effect whereas 191G>A (R64Q), 341T>C (I114T), 434A>C (E145P), and 590G>A (R197Q) each significantly reduced the metabolic activation of all three carcinogens. The effects of 845A>C (K282T) and 857G>A (G286E) varied with carcinogen as they reduced the metabolic activation of N‐OH ‐IQ and N‐OH‐ABP but increased the metabolic activation of N‐OH‐PhIP. This work was partially supported by USPHS grant CA034627.