Identification and Characterization of Functional Rat Arylamine N-acetyltransferase 3: Comparisons with Rat Arylamine N-acetyltransferases 1 and 2

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2006 Jul 11

PMID 16829624

Citations 13

Authors

Jason M Walraven

Mark A Doll

David W Hein

Affiliations

Soon will be listed here.

Abstract

Arylamine N-acetyltransferases (NATs; EC 2.3.1.5) catalyze both the N-acetylation and O-acetylation of arylamines and N-hydroxyarylamines. Humans possess two functional N-acetyltransferase genes, NAT1 and NAT2, as well as a nonfunctional pseudogene, NATP. Previous studies have identified Nat1 and Nat2 genes in the rat. In this study, we identified and characterized a third rat N-acetyltransferase gene (Nat3) consisting of a single open reading frame of 870 base pairs encoding a 290-amino acid protein, analogous to the previously identified human and rat N-acetyltransferase genes. Rat Nat3 nucleotide sequence was 77.2 and 75.9% identical to human NAT1 and NAT2, respectively. Rat Nat3 amino acid sequence was 68.6 and 67.2% identical to human NAT1 and NAT2, respectively. Rat Nat1, Nat2, and Nat3 were each cloned and recombinantly expressed in Escherichia coli. Recombinant rat Nat3 exhibited thermostability intermediate between recombinant rat Nat1 and Nat2. Recombinant rat Nat3 was functional and catalyzed the N-acetylation of several arylamine substrates, including 3-ethylaniline, 3,5-dimethylaniline, 5-aminosalicylic acid, 4-aminobiphenyl, 4,4'-methylenedianiline, 4,4'-methylenebis(2-chloroaniline), and 2-aminofluorene, and the O-acetylation of N-hydroxy-4-aminobiphenyl. The relative affinities of arylamine carcinogens such as 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, and 2-aminofluorene for N- and O-acetylation via recombinant rat Nat3 were comparable with recombinant rat Nat1 and higher than for recombinant rat Nat2. This study is the first to report a third arylamine N-acetyltransferase isozyme with significant functional capacity.

Citing Articles

Acetylator Genotype-Dependent Dyslipidemia in Rats Congenic for -Acetyltransferase 2.

Hong K, Doll M, Lykoudi A, Salazar-Gonzalez R, Habil M, Walls K Toxicol Rep. 2020; 7:1319-1330.

PMID: 33083237 PMC: 7553889. DOI: 10.1016/j.toxrep.2020.09.011.

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Oesch F, Fabian E, Landsiedel R Arch Toxicol. 2018; 92(8):2411-2456.

PMID: 29916051 PMC: 6063329. DOI: 10.1007/s00204-018-2232-x.

Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation.

Hein D, Zhang X, Doll M Toxicol Lett. 2017; 283:100-105.

PMID: 29180287 PMC: 5745265. DOI: 10.1016/j.toxlet.2017.11.028.

Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism.

Stepp M, Doll M, Samuelson D, Sanders M, States J, Hein D BMC Cancer. 2017; 17(1):233.

PMID: 28359264 PMC: 5374573. DOI: 10.1186/s12885-017-3221-9.

Treatment of Rats with Apocynin Has Considerable Inhibitory Effects on Arylamine N-Acetyltransferase Activity in the Liver.

Francis S, Laurieri N, Nwokocha C, Delgoda R Sci Rep. 2016; 6:26906.

PMID: 27242013 PMC: 4886258. DOI: 10.1038/srep26906.

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