RT Journal Article
SR Electronic
T1 Phenotype of the Most Common “Slow Acetylator” Arylamine N-Acetyltransferase 1 Genetic Variant (NAT1*14B) Is Substrate-Dependent
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 198
OP 204
DO 10.1124/dmd.111.041855
VO 40
IS 1
A1 Lori M. Millner
A1 Mark A. Doll
A1 Jian Cai
A1 J. Christopher States
A1 David W. Hein
YR 2012
UL http://dmd.aspetjournals.org/content/40/1/198.abstract
AB 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.