The human xenobiotic-metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) is irreversibly inhibited by inorganic (Hg2+) and organic mercury (CH3Hg+): mechanism and kinetics.
Human arylamine N-acetyltransferase 1 (NAT1) is a xenobiotic-metabolizing enzyme that biotransforms aromatic amine chemicals. We show here that biologically-relevant concentrations of inorganic (Hg2+) and organic (CH3Hg+) mercury inhibit the biotransformation functions of NAT1. Both compounds react irreversibly with the active-site cysteine of NAT1 (half-maximal inhibitory concentration (IC50)=250 nM and kinact=1.4x10(4) M(-1) s(-1) for Hg2+ and IC50=1.4 microM and kinact=2x10(2) M(-1) s(-1) for CH3Hg+). Exposure of lung epithelial cells led to the inhibition of cellular NAT1 (IC50=3 and 20 microM for Hg2+ and CH3Hg+, respectively). Our data suggest that exposure to mercury may affect the biotransformation of aromatic amines by NAT1.
Ragunathan
Nilusha
N
University of Paris Diderot-Paris 7, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France.
Busi
Florent
F
Pluvinage
Benjamin
B
Sanfins
Elodie
E
Dupret
Jean-Marie
JM
Rodrigues-Lima
Fernando
F
Dairou
Julien
J
D000105:Acetyl Coenzyme A / Q000494:pharmacology; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008168:Lung / Q000166:cytology; D008628:Mercury / Q000494:pharmacology*; D008767:Methylmercury Compounds / Q000494:pharmacology*; D015262:Xenobiotics / Q000378:metabolism*
D007527:Isoenzymes; D008767:Methylmercury Compounds; D015262:Xenobiotics; D000105:Acetyl Coenzyme A; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D008628:Mercury; D005978:Glutathione