Phenotype of the most common "slow acetylator" arylamine N-acetyltransferase 1 genetic variant (NAT1*14B) is substrate-dependent.
Human arylamine N-acetyltransferase 1 (NAT1) is a phase II cytosolic enzyme responsible for the activation or deactivation of many arylamine compounds including pharmaceuticals and environmental carcinogens. NAT1 is highly polymorphic and has been associated with altered risk toward many cancers. NAT1*14B is characterized by a single nucleotide polymorphism in the coding region (rs4986782; 560G>A; R187Q). NAT1*14B is associated with higher frequency of smoking-induced lung cancer and is the most common "slow acetylator" arylamine NAT1 genetic variant. Previous studies have reported decreased N- and O-acetylation capacity and increased proteasomal degradation of NAT1 14B compared with the referent, NAT1 4. The current study is the first to investigate NAT1*14B expression using constructs that completely mimic NAT1 mRNA by including the 5'- and 3'-untranslated regions, together with the open reading frame of the referent, NAT1*4, or variant, NAT1*14B. Our results show that NAT1 14B is not simply associated with "slow acetylation." NAT1 14B-catalyzed acetylation phenotype is substrate-dependent, and NAT1 14B exhibits higher N- and O-acetylation catalytic efficiency as well as DNA adducts after exposure to the human carcinogen 4-aminobiphenyl.
Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
Lori M
LM
Millner
Mark A
MA
Doll
Jian
J
Cai
J Christopher
JC
States
David W
DW
Hein
D000107:Acetylation; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism*; D016466:CHO Cells; D002384:Catalysis; D006224:Cricetinae; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D013379:Substrate Specificity / Q000502:physiology; D013997:Time Factors
D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1