TOXI 85 |
| Arylamine N-acetyltransferases (NATs) catalyze AcCoA-dependent acetylation reactions that detoxify arylamines and bioactivate N-arylhydroxylamines. Nitrosoarenes are formed in vivo as oxidation products of arylamines and N-arylhydroxylamines. Incubation of human NAT1 with an equivalent concentration of 4-nitrosobiphenyl, a metabolite of the arylamine carcinogen, 4-aminobiphenyl, caused 77% inactivation of NAT1 within 60 seconds. The inactivation was only partially prevented by a 500-5000 fold excess of GSH. Treatment of HeLa cells with 4-nitrosobiphenyl (0.02 mM) caused 42% loss of NAT1 activity, but no loss of glyceraldehyde phosphate dehydrogenase activity, in 15 minutes. Longer exposure times resulted in greater loss of enzyme activity. MS/MS analysis indicated that 4-nitrosobiphenyl treatment of HeLa cells in which NAT1 had been overexpressed resulted in (4-biphenyl)sulfinamide adduct formation with the catalytically essential Cys68 of NAT1. This is consistent with the (4-biphenyl)sulfinamide adduct formation that occurred upon inactivation of NAT1 with 4-nitrosobiphenyl in vitro. It is concluded that NAT1 is a target for adduction by nitrosoarene metabolites of certain environmental arylamines. |
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Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster
Division of Chemical Toxicology |