Role of Human N-Acetyltransferase 2 Genetic Polymorphism on Aromatic Amine Carcinogen-Induced DNA Damage and Mutagenicity in a Chinese Hamster Ovary Cell Mutation Assay

被引：11

作者：

Baldauf, Kristin J. ^{[1
,2
,3
]}

Salazar-Gonzalez, Rao A. ^{[1
,2
]}

Doll, Mark A. ^{[1
,2
]}

Pierce, William M., Jr. ^{[1
,2
]}

States, J. Christopher ^{[1
,2
]}

Hein, David W. ^{[1
,2
]}

机构：

[1] Dept Pharmacol & Toxicol, Louisville, KY USA

[2] James Graham Brown Canc Ctr, Louisville, KY USA

[3] Abbvie Pharmaceut, N Chicago, IL USA

来源：

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS | 2020年 / 61卷 / 02期

基金：

美国国家卫生研究院;

关键词：

N-acetyltransferase; 2; genetic polymorphism; 4-aminobiphenyl; 2-aminofluorene; MAMMARY-GLAND CARCINOGENESIS; HETEROCYCLIC AMINES; MOLECULAR-GENETICS; ADDUCT LEVELS; NAT2; 2-AMINOFLUORENE; GENOTOXICITY; ACETYLATION; METABOLISM; 2-ACETYLAMINOFLUORENE;

D O I：

10.1002/em.22331

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

摘要：

Carcinogenic aromatic amines such as 4-aminobiphenyl (ABP) and 2-aminofluorene (AF) require metabolic activation to form electrophilic intermediates that mutate DNA leading to carcinogenesis. Bioactivation of these carcinogens includes N-hydroxylation catalyzed by CYP1A2 followed by O-acetylation catalyzed by arylamine N-acetyltransferase 2 (NAT2). To better understand the role of NAT2 genetic polymorphism in ABP- and AF-induced mutagenesis and DNA damage, nucleotide excision repair-deficient (UV5) Chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. ABP and AF both caused significantly (P < 0.001) greater mutagenesis measured at the hypoxanthine phosphoribosyl transferase (hprt) locus in the UV5/CYP1A2/NAT2*4 acetylator cell line compared to the UV5, UV5/CYP1A2, and UV5/CYP1A2/NAT2*5B cell lines. ABP- and AF-induced hprt mutant cDNAs were sequenced and over 80% of the single-base substitutions were at G:C base pairs. DNA damage also was quantified by gamma H2AX in-cell western assays and by identification and quantification of the two predominant DNA adducts, N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) and N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) by liquid chromatography-mass spectrometry. DNA damage and adduct levels were dose-dependent, correlated highly with levels of hprt mutants, and were significantly (P < 0.0001) greater in the UV5/CYP1A2/NAT2*4 rapid acetylator cell line following treatment with ABP or AF as compared to all other cell lines. Our findings provide further clarity on the importance of O-acetylation in CHO mutagenesis assays for aromatic amines. They provide evidence that NAT2 genetic polymorphism modifies aromatic amine-induced DNA damage and mutagenesis that should be considered in human risk assessments following aromatic amine exposures. Environ. Mol. Mutagen. 2019. (c) 2019 Wiley Periodicals, Inc.

引用

页码：235 / 245

页数：11

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