Identification of N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine as the major adduct formed by the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, with DNA

Lin, Dong; Kaderlik, Keith R.; Turesky, Robert J.; Miller, Dwight W.; Lay, Jackson O.; Kadlubar, Fred F.

doi:10.1021/tx00029a016

Cited by 164 publications

(175 citation statements)

References 29 publications

Supporting

Mentioning

172

Contrasting

Order By: Relevance

“…A single PhIP-DNA adduct, N-(deoxyguanosin-8-yl)-PhIP, was identified in hamster colon. This is also the major DNA adduct formed after PhIP treatment of rats (Lin et al 1992;Purewal et al 2000a) and cynomolgus monkeys (Snyderwine et al 1993). The levels of N-(deoxyguanosin-8-yl)-PhIP, i.e.…”

Section: Discussionmentioning

confidence: 98%

DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

Steffensen¹,

Fretland²,

Paulsen³

et al. 2000

Pharmacology & Toxicology

View full text Add to dashboard Cite

Epidemiological studies indicate that rapid acetylators with a high intake of well-done red meat have an increased risk of colorectal cancer. Arylamine N-acetyltransferase enzymes (E.C. 2.3.1.5) activate carcinogenic heterocyclic amines found in the crust of fried meat via O-acetylation of their N-hydroxylamines to reactive intermediates that bind covalently to DNA and produce mutations. Syrian hamsters as well as humans express two N-acetyltransferase isozymes (NAT1 and NAT2) which differ in substrate specificity and genetic control. Nucleic acid substitutions in the NAT2 gene segregate individuals into rapid, intermediate and slow acetylator phenotypes. In the present paper, we examined the role of the polymorphic NAT2 acetylator genotype in carcinogenesis induced by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by comparing Syrian hamster lines congenic at the NAT2 locus. No differences were found between rapid and slow acetylator congenic hamsters in levels of intestinal PhIP-DNA adducts. In contrast to previous studies in rats, no carcinogen-related induction of the preneoplastic lesions aberrant crypt foci or tumors was found in the intestines of rapid and slow acetylator congenic Syrian hamsters administered PhIP or IQ.

show abstract

Section: Discussionmentioning

confidence: 98%

DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

Steffensen¹,

Fretland²,

Paulsen³

et al. 2000

Pharmacology & Toxicology

View full text Add to dashboard Cite

show abstract

“…N-Hydroxy PhIP and the N-acetoxy derivative of N-hydroxy PhIP were synthesized as described by Lin et al [1992]. The adduct standard was synthesized as follows ( Fig.…”

Section: Pdgp-phipmentioning

confidence: 99%

Carcinogen–DNA adducts in human breast epithelial cells

Gorlewska-Roberts

Green

Fares

et al. 2002

Environ and Mol Mutagen

View full text Add to dashboard Cite

Diet and environmental exposures are often regarded as significant etiologic factors in human breast cancer. Chemicals that may be involved in these exposures include heterocyclic amines, aromatic amines, and polycyclic aromatic hydrocarbons, which also serve as strong mammary carcinogens in different animal models. In this study, we chose to quantify the major DNA adducts derived from one member of each of these classes of carcinogens, that is, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 4-aminobiphenyl (ABP), and benzo[a]pyrene (B[a]P), respectively, in DNA isolated from exfoliated ductal epithelial cells in human breast milk. Milk was collected from healthy, nonsmoking mothers. The isolated DNA was digested to 3Ј nucleotides and subjected to 32 P-postlabeling. Adduct enrichment was achieved using Oasis Sep-Paks and the analyses were conducted by HPLC using radiometric detection. Critical to the analyses were the syntheses of bis(phosphate) standards for the C8-dG adducts of PhIP and ABP, and the N 2 -dG adduct of B[a]P, which were added to each reaction as UV markers. Of the 64 samples analyzed, adducts were found in 31 samples. Thirty samples contained detectable levels of PhIP adducts, with a mean value of 4.7 adducts/10 7 nucleotides; 18 were positive for ABP adducts with a mean value of 4.7 adducts/ 10 7 nucleotides; and 13 were found to contain B[a]P adducts with a mean level of 1.9 adducts/ 10 7 nucleotides. These data indicate that women are exposed to several classes of dietary and environmental carcinogens and that these carcinogens react with DNA in breast ductal epithelial cells, the cells from which most breast cancers arise.

show abstract

“…TLC was performed using the solvent system reported previously [Lin et al, 1992]. Adducts were visualized as dark spots on X-ray film after subjecting the TLC plates to autoradiography.…”

Section: P-postlabeling and Tlc Separationmentioning

confidence: 99%

Evidence for the presence of mutagenic arylamines in human breast milk and DNA adducts in exfoliated breast ductal epithelial cells

Thompson

DeMarini

Kadlubar

et al. 2002

Environ and Mol Mutagen

Self Cite

View full text Add to dashboard Cite

Aromatic and heterocyclic amines are ubiquitous environmental mutagens present in combustion emissions, fried meats, and tobacco smoke, and are suspect human mammary carcinogens. To determine the presence of arylamines in breast tissue and fluid, we examined exfoliated breast ductal epithelial cells for DNA adducts and matched human milk samples for mutagenicity. Breast milk was obtained from 50 women who were 4 -6 weeks postpartum, and exfoliated epithelial-cell DNA was evaluated for bulky, nonpolar DNA adducts by 32 P-postlabeling and thin-layer chromatography. Milk was processed by acid hydrolysis, and the extracted organics were examined in the standard plate-incorporation Ames Salmonella assay using primarily strain YG1024, which detects frameshift mutations and overexpresses aryl amine N-acetyltransferase. DNA adducts were identified in 66% of the specimens, and bulky adducts migrated in a pattern similar to that of 4-aminobiphenyl standards. The distribution of adducts did not vary by NAT2 genotype status. Of whole milk samples, 88% (22/25) had mutagenic activity.Among the samples for which we had both DNA adduct and mutagenicity data, 58% (14/19) of the samples with adducts were also mutagenic, and 85% (11/13) of the mutagenic samples had adducts. Quantitatively, no correlation was observed between the levels of adducts and the levels of mutagenicity. Separation of the milk showed that mutagenic activity was found in 69% of skimmed milk samples but in only 29% of the corresponding milk fat samples, suggesting that the breast milk mutagens were moderately polar molecules. Chemical fractionation showed that mutagenic activity was found in 67% (4/6) of the basic fractions but in only 33% (2/6) of acidic samples, indicating that the mutagens were primarily basic compounds, such as arylamines. Although pilot in nature, this study corroborates previous findings of significant levels of DNA adducts in breast tissue and mutagenicity in human breast milk and indicates that breast milk mutagens may be moderately polar basic compounds, such as arylamines.

show abstract

Identification of N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine as the major adduct formed by the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, with DNA

Cited by 164 publications

References 29 publications

DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

Carcinogen–DNA adducts in human breast epithelial cells

Evidence for the presence of mutagenic arylamines in human breast milk and DNA adducts in exfoliated breast ductal epithelial cells

Contact Info

Product

Resources

About