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| Content Provider | PubMed Central |
|---|---|
| Author | Millner, Lori M. Doll, Mark A. Stepp, Marcus W. Hein, David W. States, J.Christopher |
| Copyright Year | 2012 |
| Abstract | N-acetyltransferase 1 (NAT1) catalyzes N-acetylation of arylamines as well as the O-acetylation of N-hydroxylated arylamines. O-acetylation leads to the formation of electrophilic intermediates that result in DNA adducts and mutations. NAT1*10 is the most common variant haplotype and is associated with increased risk for numerous cancers. NAT1 is transcribed from a major promoter, NATb, and an alternative promoter, NATa, resulting in messenger RNAs (mRNAs) with distinct 5′-untranslated regions (UTRs). To best mimic in vivo metabolism and the effect of NAT1*10 polymorphisms on polyadenylation usage, pcDNA5/Flp recombination target plasmid constructs were prepared for transfection of full-length human mRNAs including the 5′-UTR derived from NATb, the open reading frame and 888 nucleotides of the 3′-UTR. Following stable transfection of NAT1*4, NAT1*10 and an additional NAT1*10 variant (termed NAT1*10B) into nucleotide excision repair-deficient Chinese hamster ovary cells, N- and O-acetyltransferase activity (in vitro and in situ), mRNA and protein expression were higher in cells transfected with NAT1*10 and NAT1*10B than in cells transfected with NAT1*4 (P < 0.05). Consistent with NAT1 expression and activity, cytotoxicity and hypoxanthine phosphoribosyl transferase mutants following 4-aminobiphenyl exposures were higher in NAT1*10 than in NAT1*4 transfected cells. Ribonuclease protection assays showed no difference between NAT1*4 and NAT1*10. However, protection of one probe by NAT1*10B was not observed with NAT1*4 or NAT1*10, suggesting additional mechanisms that regulate NAT1*10B. The higher mutants in cells transfected with NAT1*10 and NAT1*10B are consistent with an increased cancer risk for individuals possessing NAT1*10 haplotypes. |
| Related Links | http://dx.doi.org/10.1093/carcin/bgr273 |
| Ending Page | 355 |
| Page Count | 8 |
| Starting Page | 348 |
| File Format | |
| ISSN | 01433334 |
| e-ISSN | 14602180 |
| Journal | Carcinogenesis |
| Issue Number | 2 |
| Volume Number | 33 |
| Language | English |
| Publisher | Oxford University Press |
| Publisher Date | 2012-02-01 |
| Access Restriction | Open |
| Rights Holder | Oxford University Press |
| Subject Keyword | Cancer Research Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Cancer Research |
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