Impairment of the activity of the xenobiotic-metabolizing enzymes arylamine N-acetyltransferases 1 and 2 (NAT1/NAT2) by peroxynitrite in mouse skeletal muscle cells.
Reactive nitrogen species and their by-products, such as peroxynitrite, modulate many physiological functions of skeletal muscle. Peroxynitrite generation occuring under specific conditions, such as inflammation, may also lead to skeletal muscle dysfunction and pathologies. Arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes (XMEs) involved in the detoxification and/or metabolic activation of several drugs and chemicals. In addition to other XMEs, such as gluthatione S-transferases or cytochromes P450, NAT enzymes are expressed in skeletal muscle. We show here that functional NAT1 and NAT2 isoforms are expressed in mouse myotubes and that peroxynitrite may impair their activity in these cells. We show that this inactivation is likely due to the irreversible modification of NATs catalytic cysteine residue in vivo. Our results suggest that peroxynitrite-dependent inactivation of muscle XMEs such as NATs may contribute to muscle dysfunction by impairing the biotransformation activity of this key cellular defense enzyme system.
Dairou
Julien
J
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, EA 1553, Université Denis Diderot-Paris 7, Case 7073, 75005 Paris, France.
Dupret
Jean-Marie
JM
Rodrigues-Lima
Fernando
F
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001191:Arylamine N-Acetyltransferase; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology*; D020030:Nitric Oxide Donors / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D007527:Isoenzymes; D020030:Nitric Oxide Donors; C432411:Slc38a1 protein, mouse; D015262:Xenobiotics; D030421:Peroxynitrous Acid; C002385:linsidomine; D000105:Acetyl Coenzyme A; D008981:Molsidomine; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D005978:Glutathione