ArticleEnvironmental health perspectives2010
Cadmium alters the biotransformation of carcinogenic aromatic amines by arylamine N-acetyltransferase xenobiotic-metabolizing enzymes: molecular, cellular, and in vivo studies.
Article in Environmental health perspectives, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 22 citations in OpenAlex.
- Hexavalent chromium increases the metabolism and genotoxicity of aromatic amine carcinogens 4-aminobiphenyl and β-naphthylamine in immortalized human lung epithelial cells.Toxicology and applied pharmacology · 2022Article
- Population variability of rhesus macaque (Macaca mulatta) NAT1 gene for arylamine N-acetyltransferase 1: Functional effects and comparison with human.Scientific reports · 2019Article
- Untargeted polar metabolomics of transformed MDA-MB-231 breast cancer cells expressing varying levels of human arylamineMetabolomics : Official journal of the Metabolomic Society · 2016Article
- Article
- Characterization of the interaction between cadmium and chlorpyrifos with integrative techniques in incurring synergistic hepatoxicity.PloS one · 2013Article
- Cadmium affects toxicokinetics of pyrene in the collembolan Folsomia candida.Ecotoxicology (London, England) · 2012Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCadmium (Cd) is a carcinogenic heavy metal of environmental concern. Exposure to both Cd and carcinogenic organic compounds, such as polycyclic aromatic hydrocarbons or aromatic amines (AAs), is a common environmental problem. Human arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that play a key role in the biotransformation of AA carcinogens. Changes in NAT activity have long been associated with variations in susceptibility to different cancers in relation with exposure to certain AAs.
objectiveWe explored the possible interactions between Cd and the NAT-dependent biotransformation of carcinogenic AAs.
methodsWe exposed purified enzymes, lung epithelial cells, and mouse models to Cd and subsequently analyzed NAT-dependent metabolism of AAs.
resultsWe found that Cd, at biologically relevant concentrations, impairs the NAT-dependent acetylation of carcinogenic AAs such as 2-aminofluorene (2-AF) in lung epithelial cells. NAT activity was strongly impaired in the tissues of mice exposed to Cd. Accordingly, mice exposed to Cd and 2-AF displayed altered in vivo toxicokinetics with a significant decrease (~ 50%) in acetylated 2-AF in plasma. We found that human NAT1 was rapidly and irreversibly inhibited by Cd [median inhibitory concentration (IC₅₀) ≈ 55 nM; rate inhibition constant (k(inact)) = 5 × 10⁴ M⁻¹ • sec⁻¹], with results of acetyl coenzyme A (acetyl-CoA) protection assays indicating that Cd-mediated inhibition was due to the reaction of metal with the active-site cysteine residue of the enzyme. We found similar results for human NAT2, although this isoform was less sensitive to inactivation (IC₅₀ ≈ 1 μM; k(inact) = 1 × 10⁴ M⁻¹ • sec⁻¹).
conclusionsOur data suggest that Cd can alter the metabolism of carcinogenic AAs through the impairment of the NAT-dependent pathway, which may have important toxicological consequences.
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