Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant R01-CA034627]; the National Institutes of Health National Institute for Environmental Health Sciences [Grants T32-ES011564, P30-ES014443]; and the Department of Defense Breast Cancer Research Program [Grant BC083107].
Portions of this work constitute partial fulfillment of the requirements for the degree of Doctor of Philosophy in pharmacology and toxicology: Millner LM (2011) Functional Analysis of N-Acetyltransferase (NAT1*14B and NAT1*10) in Complete NATb and NATa mRNA. Doctoral dissertation, University of Louisville, Louisville, KY.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- NAT1
- N-acetyltransferase 1
- CoASAc
- acetyl CoA
- PABA
- p-aminobenzoic acid
- UTR
- untranslated region
- ABP
- 4-aminobiphenyl
- HPLC
- high-performance liquid chromatography
- N-OH-ABP
- N-hydroxy-4-aminobiphenyl
- ORF
- open reading frame
- CHO
- Chinese hamster ovary
- FRT
- Flp recombination target
- α-MEM
- α-modified minimal essential medium
- ACN
- acetonitrile
- dG
- deoxyguanosine
- PBS
- phosphate-buffered saline.
- Received July 20, 2011.
- Accepted October 18, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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