Kinetics of arylamine N-acetyltransferase in tissues from human breast cancer

Lee, J. H.; Chung, Jing-Gung; Lai, J. M.; Levy, Gerald N.; Weber, Wendell W.

doi:10.1016/s0304-3835(96)04491-6

Cited by 23 publications

(14 citation statements)

References 21 publications

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“…The use of selective ER modulators (SERMs) has had an important impact on the improved prognosis for patients with ER-positive breast cancer, with tamoxifen being the most widely prescribed SERM for ER-positive breast cancer treatment. Tamoxifen has been shown to inhibit the enzymic activity of NAT1, both in tissue cytosols from breast cancer tissues (Lee et al, 1997) and in vitro using purified recombinant NAT1 enzyme, although it does not act as a substrate for acetylation (Kawamura et al, 2007, in preparation).…”

Section: Introductionmentioning

confidence: 99%

Arylamine N‐acetyltransferase 1 expression in breast cancer cell lines: A potential marker in estrogen receptor‐positive tumors

Wakefield

Robinson

Long

et al. 2007

Genes Chromosomes & Cancer

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The prognosis for patients with estrogen receptor (ER)-positive breast cancer has improved significantly with the prescription of selective ER modulators (SERMs) for ER-positive breast cancer treatment. However, only a proportion of ER-positive tumors respond to SERMs, and resistance to hormonal therapies is still a major problem. Detailed analysis of published microarray studies revealed a positive correlation between overexpression of the drug metabolizing enzyme arylamine N-acetyltransferase type 1 (NAT1) and ER positivity, and increasing evidence supports a biological role for NAT1 in breast cancer progression. We have tested a range of ER-positive and ER-negative breast cancer cell lines for NAT1 enzyme activity, and monitored promoter and polyadenylation site usage. Amongst ER-positive lines, NAT1 activities ranged from 202 +/- 28 nmol/min/mg cellular protein (ZR-75-1) to 1.8 +/- 0.4 nmol/min/mg cellular protein (MCF-7). The highest levels of NAT1 activity could not be attributed to increased NAT1 gene copy number; however, we did detect differences in NAT1 promoter and polyadenylation site usage amongst the breast tumor-derived lines. Thus, whilst all cell lines tested accumulated transcripts derived from the proximal promoter, the line expressing NAT1 most highly additionally initiated transcripts initiating at a more distal, "tissue"-specific promoter. These data pave the way for investigating NAT1 transcripts as candidate prognostic markers in ER-positive breast cancer.

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Section: Introductionmentioning

confidence: 99%

Arylamine N‐acetyltransferase 1 expression in breast cancer cell lines: A potential marker in estrogen receptor‐positive tumors

Wakefield

Robinson

Long

et al. 2007

Genes Chromosomes & Cancer

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“…Bioactivation usually involves two or more enzymatic reactions, typically oxidation or hydroxylation, followed by conjugation or hydrolysis. Certain enzymes involved in the metabolism of carcinogens are expressed in normal breast tissue [Lee et al, 1996;Williams and Philips, 2001]. Polycyclic aromatic hydrocarbons are activated by cytochromes P4501A1 and P4501B1, and reactive intermediates are detoxified by glutathione-S-transferases.…”

Section: Introductionmentioning

confidence: 99%

Carcinogen–DNA adducts in human breast epithelial cells

Gorlewska-Roberts

Green

Fares

et al. 2002

Environ and Mol Mutagen

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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.

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“…Further mechanisms of NAT1 inhibition involve direct modifications of the catalytic cysteine residue either by oxidation (Atmane et al, 2003) or adduct formation with reactive intermediates of NAT1 substrates (Butcher et al, 2000a;Liu et al, 2009). In addition, several nonsubstrates such as tamoxifen (Lee et al, 1997) and cisplatin (Ragunathan et al, 2008) are known to down-regulate its activity. It is noteworthy that the latter are commonly used as antitumor agents, and recent data suggest that cisplatin-induced NAT1 inactivation contributes to their beneficial effects, not least because of increasing evidence for a dysregulation of NAT1 in certain cancer cells (Adam et al, 2003;Wakefield et al, 2008).…”

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confidence: 99%

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

Bonifas

Scheitza²,

Clemens³

et al. 2010

J Pharmacol Exp Ther

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N-acetyltransferase 1 (NAT1)-mediated N-acetylation in keratinocytes is an important detoxification pathway for the hair dye ingredient para-phenylenediamine (PPD). Because NAT1 can be regulated by various exogenous compounds, including some NAT1 substrates themselves, we investigated NAT1 expression in keratinocytes and the interactions between PPD and NAT1. NAT1 activity was found to be cell-cycle phasedependent. Maximum NAT1 activities (mean: 49.7 nmol/mg/ min) were estimated when HaCaT keratinocytes were arrested in G 0 /G 1 phase, whereas nonsynchronized cells showed the lowest activities (mean: 28.9 nmol/mg/min). It is noteworthy that we also found an accelerated progression through the cell cycle in HaCaT cells with high NAT1 activities. This evidence suggests an association between NAT1 and proliferation in keratinocytes. Regarding the interaction between NAT1 and PPD, we found that keratinocytes N-acetylate PPD; however, this N-acetylation was saturated with increasing PPD concentrations. HaCaT cultured in medium supplemented with PPD (10 -200 M) for 24 h showed a significant concentration-dependent decrease (17-50%) in NAT1 activity. PPD also induced down-regulation of NAT1 activity in human primary keratinocytes. Western blot studies using a NAT1-specific antibody in HaCaT showed that the loss of enzyme activity was associated with a decline in the amount of NAT1 protein, whereas no changes in the amounts of NAT1 P1 (NATb)-dependent mRNA were found by quantitative reverse transcription-polymerase chain reaction analysis, suggesting the involvement of a substrate-dependent mechanism of NAT1 down-regulation. In conclusion, these data show that overall N-acetylation capacity of keratinocytes and consequently detoxification capacities of human skin is modulated by the presence of NAT1 substrates and endogenously by the cell proliferation status of keratinocytes.

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Kinetics of arylamine N-acetyltransferase in tissues from human breast cancer

Cited by 23 publications

References 21 publications

Arylamine N‐acetyltransferase 1 expression in breast cancer cell lines: A potential marker in estrogen receptor‐positive tumors

Arylamine N‐acetyltransferase 1 expression in breast cancer cell lines: A potential marker in estrogen receptor‐positive tumors

Carcinogen–DNA adducts in human breast epithelial cells

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

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