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Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. 2003

Cinzia Magagnotti, and Roberta Pastorelli, and Simonetta Pozzi, and Bruno Andreoni, and Roberto Fanelli, and Luisa Airoldi
Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine derived from food, possibly involved in human carcinogenesis. We evaluated the formation of PhIP-DNA adducts in lymphocytes from 76 incident colorectal cancer patients likely to be exposed to dietary PhIP. To address the role of the metabolic polymorphisms relevant to PhIP-DNA adduct formation, the patients were genotyped for common polymorphisms in the N-acetyltransferase (NAT1 and NAT2), sulfotransferase (SULT1A1) and glutathione S-transferase (GSTM1 and GSTA1) genes. PhIP released from adducted DNA after hydrolysis was quantitated by liquid chromatography-tandem mass spectrometry. Overall, adducts were 3.24 +/- 3.58/10(8) nucleotides (mean +/- SD); they were not related to sex, smoking habits or age, though levels were not significantly higher in smokers, young subjects and high meat consumers. High vegetable intake significantly reduced PhIP-DNA adducts (Mann-Whitney U, p = 0.044). Individuals with the GSTM1 null genotype showed colon cancer onset at earlier age (58.8 +/- 1.8 vs. 63.5 +/- 1.6 years; Mann-Whitney U, p = 0.047). None of the genetic polymorphisms studied significantly affected PhIP-DNA adducts. However, individuals carrying 2 mutated GSTA1 alleles and younger than the median age had higher adduct levels than homozygous wild-type and heterozygous ones (Kruskal-Wallis p = 0.0008). In conclusion, these preliminary data indicate that PhIP-DNA adducts are formed in people likely to be exposed to this carcinogen through the diet, suggesting this biomarker may be useful to detect human exposure and DNA damage. Overall, the genetic polymorphisms considered had limited effect on PhIP-DNA levels, but young people with lower detoxification capacity may form a subgroup particularly susceptible to dietary carcinogen.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008214 Lymphocytes White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS. Lymphoid Cells,Cell, Lymphoid,Cells, Lymphoid,Lymphocyte,Lymphoid Cell
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D011110 Polymorphism, Genetic The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level. Gene Polymorphism,Genetic Polymorphism,Polymorphism (Genetics),Genetic Polymorphisms,Gene Polymorphisms,Polymorphism, Gene,Polymorphisms (Genetics),Polymorphisms, Gene,Polymorphisms, Genetic
D012150 Polymorphism, Restriction Fragment Length Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment. RFLP,Restriction Fragment Length Polymorphism,RFLPs,Restriction Fragment Length Polymorphisms
D004032 Diet Regular course of eating and drinking adopted by a person or animal. Diets
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015179 Colorectal Neoplasms Tumors or cancer of the COLON or the RECTUM or both. Risk factors for colorectal cancer include chronic ULCERATIVE COLITIS; FAMILIAL POLYPOSIS COLI; exposure to ASBESTOS; and irradiation of the CERVIX UTERI. Colorectal Cancer,Colorectal Carcinoma,Colorectal Tumors,Neoplasms, Colorectal,Cancer, Colorectal,Cancers, Colorectal,Carcinoma, Colorectal,Carcinomas, Colorectal,Colorectal Cancers,Colorectal Carcinomas,Colorectal Neoplasm,Colorectal Tumor,Neoplasm, Colorectal,Tumor, Colorectal,Tumors, Colorectal
D016133 Polymerase Chain Reaction In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. Anchored PCR,Inverse PCR,Nested PCR,PCR,Anchored Polymerase Chain Reaction,Inverse Polymerase Chain Reaction,Nested Polymerase Chain Reaction,PCR, Anchored,PCR, Inverse,PCR, Nested,Polymerase Chain Reactions,Reaction, Polymerase Chain,Reactions, Polymerase Chain
D018736 DNA Adducts The products of chemical reactions that result in the addition of extraneous chemical groups to DNA. DNA Adduct,Adduct, DNA,Adducts, DNA

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