Cadmium alters the biotransformation of carcinogenic aromatic amines by arylamine N-acetyltransferase xenobiotic-metabolizing enzymes: molecular, cellular, and in vivo studies.
BACKGROUND
Cadmium (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.


OBJECTIVE
We explored the possible interactions between Cd and the NAT-dependent biotransformation of carcinogenic AAs.


METHODS
We exposed purified enzymes, lung epithelial cells, and mouse models to Cd and subsequently analyzed NAT-dependent metabolism of AAs.


RESULTS
We 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).


CONCLUSIONS
Our 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.
Ragunathan
Nilusha
N
Université Paris Diderot-Paris 7, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique, Paris, France.
Dairou
Julien
J
Sanfins
Elodie
E
Busi
Florent
F
Noll
Christophe
C
Janel
Nathalie
N
Dupret
Jean-Marie
JM
Rodrigues-Lima
Fernando
F
D000588:Amines / Q000378:metabolism*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology
D000588:Amines; D002273:Carcinogens; D004785:Environmental Pollutants; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; D002104:Cadmium; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C524206:Nat2 enzyme, mouse
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