Bioactivation, Mutagenicity, DNA Damage, and Oxidative Stress Induced by 3,4-Dimethylaniline

Abstract

3,4-Dimethylaniline (3,4-DMA) is present in cigarette smoke and widely used as an intermediate in dyes, drugs, and pesticides. Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human CYP1A2 and N-acetyltransferase 1 (NAT1) alleles: NAT1*4 (reference allele) or NAT1*14B (the most common variant allele) were utilized to assess 3,4-DMA N-acetylation and hypoxanthine phosphoribosyl transferase (HPRT) mutations, double-strand DNA breaks and reactive oxygen species (ROS). CHO cells expressing NAT1*4 exhibited significantly (p N-acetylation rates than CHO cells expressing NAT1*14B both in vitro and in situ. In CHO cells expressing CYP1A2 and NAT1, 3,4-DMA caused concentration-dependent increases in reactive oxygen species (ROS), double-stranded DNA damage, and HPRT mutations. CHO cells expressing NAT1*4 and NAT1*14B exhibited concentration-dependent increases in ROS following treatment with 3,4-DMA (linear trend p p NAT1*4 and NAT1*14B, respectively) that were lower than in CHO cells expressing CYP1A2 alone. DNA damage and oxidative stress induced by 3,4-DMA did not differ significantly (p >0.05) between CHO cells expressing NAT1*4 and NAT1*14B. CHO cells expressing NAT1*14B showed higher HPRT mutants (p NAT1*4. These findings confirm 3,4-DMA genotoxicity consistent with potential carcinogenicity.

Keywords

• 3,4-dimethylaniline
• NAT1
• mutations
• double strand breaks
• genotoxicity