Hepatic N-acetyltransferases: selective inactivation in vivo by a carcinogenic N-arylhydroxamic acid.
N-Hydroxy-2-acetamidofluorene (N-OH-AAF), a carcinogenic N-arylhydroxamic acid, is a selective and irreversible inhibitor of arylamine N-acetyltransferase (NAT) activity in vitro. The present study demonstrates that intraperitoneal administration of N-OH-AAF to hamsters caused an irreversible reduction of the hepatic transacetylase activity that catalyzes the transfer of the acetyl group from N-OH-AAF to 4-aminoazobenzene (AAB), but did not affect the acetyl coenzyme A (CoASAc) dependent NAT that is responsible for acetylation of p-aminobenzoic acid (PABA). A 40% loss of N-OH-AAF:AAB transacetylase activity occurred 4 hr after administration of 50 mg/kg of N-OH-AAF. To determine whether biotransformation of N-OH-AAF is a factor in determining its ability to inactivate N-OH-AAF:AAB transacetylase activity in vivo, the enzyme-inducing agent phenobarbital and the esterase/acylamidase inhibitor bis(p-nitrophenyl)phosphate (BNPP) were administered to the animals prior to the administration of N-OH-AAF. The loss of N-OH-AAF:AAB transacetylase activity was prevented by treatment of the animals with either phenobarbital or with BNPP. The ability of the esterase/acylamidase inhibitor, BNPP, to prevent the N-OH-AAF-mediated loss of transacetylase activity indicates that, in contrast to the inactivation process in vitro, esterase-catalyzed deacetylation of N-OH-AAF may be required for transacetylase inactivation in vivo. It is proposed that in vivo the endogenous acetyl donor, CoASAc, acetylates the enzyme and prevents the deacetylation of N-OH-AAF by NAT, thereby impeding the N-OH-AAF-mediated inactivation process, but facilitating enzyme inactivation by N-hydroxy-2-aminofluorene. The latter proposal was supported by the demonstration that CoASAc inhibited the in vitro inactivation of N-OH-AAF:AAB transacetylase activity by N-OH-AAF.
Smith
T J
TJ
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, 55455.
Hanna
P E
PE
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives*; D010129:4-Aminobenzoic Acid; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D006881:Hydroxyacetylaminofluorene / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus
D006881:Hydroxyacetylaminofluorene; D000105:Acetyl Coenzyme A; D015073:2-Acetylaminofluorene; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; D010129:4-Aminobenzoic Acid