Interindividual variation in the metabolic activation of heterocyclic amines and their N-hydroxy derivatives in primary cultures of human mammary epithelial cells

Stone, Elaine M.; Williams, Julia; Grover, Philip L.; Gusterson, Barry A.; Phillips, David H.

doi:10.1093/carcin/19.5.873

Cited by 36 publications

(22 citation statements)

References 34 publications

(34 reference statements)

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“…N-hydroxy-MeIQx O-acetyltransferase activity was about 4-fold higher in CYP1A2/NAT2 * 4 -transfected cells than in CYP1A2/NAT2 * 5B -transfected cells which is similar to previous studies in yeast [30] and in CHO cells [9]. Our results confirm previous studies suggesting that NAT2 is an important activation enzyme for IQ and MeIQx genotoxicity [9, 13, 20–22, 31]. Furthermore, the effect of NAT2 on both MeIQx and IQ-induced DNA adduct formation and mutagenesis was restricted to the rapid acetylator CYP1A2/NAT2 * 4 -transfected cell line at each concentration tested.…”

Section: Discussionsupporting

confidence: 92%

Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx)

Metry

Neale

Doll

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Heterocyclic amines such as 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx) are dietary carcinogens generated when meats are cooked well-done. Bioactivation includes N-hydroxylation catalyzed by cytochrome P4501A2 (CYP1A2) followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles were treated with IQ or MeIQx to examine the effect of NAT2 genetic polymorphism on IQ- or MeIQx-induced DNA adducts and mutagenesis. MeIQx and IQ both induced decreases in cell survival and significantly (p<0.001) greater number of endogenous hypoxanthine phosphoribosyl transferase (hprt) mutants in the CYP1A2/NAT2*4 than the CYP1A2/NAT2*5B cell line. IQ- and MeIQx- induced hprt mutant cDNAs were sequenced and over 85% of the mutations were single base substitutions with the remainder exon deletions likely caused by splice-site mutations. For the single-base substitutions, over 85% were at G:C base pairs. Deoxyguanosine (dG) -C8-IQ and dG-C8-MeIQx adducts were significantly (p < 0.001) greater in the CYP1A2/NAT2*4 than the CYP1A2/NAT2*5B cell line. DNA adduct levels correlated very highly with hprt mutants for both IQ and MeIQx. These results suggest substantially increased risk for IQ- and MeIQx-induced DNA damage and mutagenesis in rapid NAT2 acetylators.

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Section: Discussionsupporting

confidence: 92%

Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx)

Metry

Neale

Doll

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…A study conducted by Zhu et al (44) showed that women preferring well-done meat and had a rapid NAT2 genotype had higher levels of PhIP-DNA adducts in breast tissue than women with the slow acetylator genotype. Stone et al (27) reported that primary cultures of human mammary epithelial of DNA adducts formed by O-acetylation of HCA compared to slow acetylator cells. In the present data, we found no association for all meat, PhIP, or total mutagenic activity with breast cancer regardless of NAT2 genotype.…”

Section: Discussionmentioning

confidence: 99%

“…Between 51 and 60% of Caucasians, and a lower proportion of African Americans, have slow acetylator genotypes for NAT2 (26). In a study of human mammary epithelial cell cultures exposed to the HCAs, DNA adducts were more often observed in cells from NAT2 fast acetylators than slow acetylators (27). …”

Section: Introductionmentioning

confidence: 99%

Meat Consumption, Heterocyclic Amines, NAT2, and the Risk of Breast Cancer

et al. 2009

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Meat consumption and heterocyclic amine (HCA) intake have been inconsistently associated with breast cancer risk in epidemiologic studies. Genetic variation in N-acetyltransferase2 (NAT2) has been suggested to modify the association of meat intake with breast cancer through its influence on metabolism of HCAs. We examined associations between meat intake, HCA exposure, acetylator genotype, and breast cancer risk in a case-control study of 2,686 case women and 3,508 controls. Women were asked to report their usual intake, cooking method, and preferred doneness of specific meats. We observed no association between total meat, red meat, or chicken with breast cancer risk. Women who consumed 5 or more servings of meat per week had no increased risk of breast cancer compared to women consuming fewer than 2 servings per week (OR = 0.99, 95% CI 0.84–1.15). No statistically significant associations with breast cancer were found for individual HCAs or for total estimated mutagenic activity of meat. Results varied modestly according to menopausal status. There were no statistically significant interactions with NAT2 genotype. Results do not support an important association of HCAs with breast cancer risk, although potential biases in case-control studies should be considered.

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“…Polycyclic aromatic hydro-carbons are activated by cytochrome P-4501A1(CYP1A1), and the resulting reactive intermediates are detoxified by glutatione-S-transferases (GSTs). These enzymes are expressed in normal breast tissue as well as in breast tumours (Sadreih et al, 1996;Lee et al, 1997;Stone et al, 1998). Individuals who are homozygous for the null-GSTM1 or null-GSTT1 genotypes lack the respective enzyme functions (Seidegaard et al, 1986;Pemble et al, 1994).…”

mentioning

confidence: 99%

Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma

et al. 2003

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Glutathione S-transferase Theta1 and Mu1 (GSTT1 and GSTM1) are involved in the metabolism and detoxification of a wide range of potential environmental carcinogens. Conversely, they contribute to tumour cell survival by detoxification of numerous products induced by cancer therapy. The authors designed a large study to investigate the susceptibility and prognostic implications of the GSTT1 and GSTM1 gene deletions in breast carcinoma. The authors used the polymerase chain reaction to characterise the variation of the GSTT1 and GSTM1 genes in 309 unrelated Tunisian patients with breast carcinoma and 242 healthy control subjects. Associations of the clinic-pathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) were assessed using univariate and multivariate analyses. A significant association was found between gene deletion of GSTT1 and the risk of early onset of breast carcinoma (OR ¼ 1.60, P ¼ 0.02). The lack of GSTT1 gene deletion was significantly associated with poor clinical response to chemotherapy (OR ¼ 2.29, P ¼ 0.03). This association was significantly higher in patients with axillary's lymph node-negative breast carcinoma (OR ¼ 12.60, P ¼ 0.005). The null-GSTT1 genotype showed a significant association with increased DFS in this selected population of patients. This association was even higher in patients carrying both null-GSTT1 and -GSTM1 genotypes. The gene deletion of GSTs may predict not only the early onset of breast carcinoma but also the clinical response to chemotherapy and the recurrence-free survival for patients with lymph nodenegative breast carcinoma.

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Interindividual variation in the metabolic activation of heterocyclic amines and their N-hydroxy derivatives in primary cultures of human mammary epithelial cells

Cited by 36 publications

References 34 publications

Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx)

Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx)

Meat Consumption, Heterocyclic Amines, NAT2, and the Risk of Breast Cancer

Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma

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