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Acetylation of putative arylamine and alkylaniline carcinogens in immortalized human fibroblasts transfected with rapid and slow acetylator N-acetyltransferase 2 haplotypes.

Abstract：

:Exposure to alkylanilines found in tobacco smoke and indoor air is associated with risk of bladder cancer. Genetic factors significantly influence the metabolism of arylamine carcinogens and the toxicological outcomes that result from exposure. We utilized nucleotide excision repair (NER)-deficient immortalized human fibroblasts to examine the effects of human N-acetyltransferase 1 (NAT1), CYP1A2, and common rapid (NAT2*4) and slow (NAT2*5B or NAT2*7B) acetylator human N-acetyltransferase 2 (NAT2) haplotypes on environmental arylamine and alkylaniline metabolism. We constructed SV40-transformed human fibroblast cells that stably express human NAT2 alleles (NAT2*4, NAT2*5B, or NAT2*7B) and human CYP1A2. Human NAT1 and NAT2 apparent kinetic constants were determined following recombinant expression of human NAT1 and NAT2 in yeast for the arylamines benzidine, 4-aminobiphenyl (ABP), and 2-aminofluorene (2-AF), and the alkylanilines 2,5-dimethylaniline (DMA), 3,4-DMA, 3,5-DMA, 2-6-DMA, and 3-ethylaniline (EA) compared with those of the prototype NAT1-selective substrate p-aminobenzoic acid and NAT2-selective substrate sulfamethazine. Benzidine, 3,4-DMA, and 2-AF were preferential human NAT1 substrates, while 3,5-DMA, 2,5-DMA, 3-EA, and ABP were preferential human NAT2 substrates. Neither recombinant human NAT1 or NAT2 catalyzed the N-acetylation of 2,6-DMA. Among the alkylanilines, N-acetylation of 3,5-DMA was substantially higher in human fibroblasts stably expressing NAT2*4 versus NAT2*5B and NAT2*7B. The results provide important insight into the role of the NAT2 acetylator polymorphism (in the presence of competing NAT1 and CYP1A2-catalyzed N-acetylation and N-hydroxylation) on the metabolism of putative alkyaniline carcinogens. The N-acetylation of two alkylanilines associated with urinary bladder cancer (3-EA and 3,5-DMA) was modified by NAT2 acetylator polymorphism.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Leggett CS,Doll MA,States JC,Hein DW

doi

10.1007/s00204-020-02901-4

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

311-319

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-020-02901-4

journal_volume

pub_type

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Acetylation of putative arylamine and alkylaniline carcinogens in immortalized human fibroblasts transfected with rapid and slow acetylator N-acetyltransferase 2 haplotypes.