Doll Mark A, Hein David W
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States.
Front Pharmacol. 2022 Feb 22;13:820082. doi: 10.3389/fphar.2022.820082. eCollection 2022.
Human arylamine N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of arylamine carcinogens such as 4-aminobiphenyl (ABP), and following N-hydroxylation, the O-acetylation of N-hydroxy-arylamine carcinogens such as N-hydroxy-ABP (N-OH-ABP). Genetic polymorphisms in NAT1 are linked to cancer susceptibility following exposures. The effects of individual single nucleotide polymorphisms (SNPs) in the NAT1 coding exon on Michaelis-Menten kinetic constants was assessed for ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activity following transfection of human NAT1 into COS-1 cells (SV40-transformed African green monkey kidney cells). NAT1 coding region SNPs 97C > T (rs56318881) (R33stop), 190C > T (rs56379106) (R64W), 559C > T (rs5030839) (R187stop) and 752A > T (rs56172717) (D251V) reduced ABP N- acetyltransferase and N-OH-ABP O-acetyltransferase activity below detection. 21T > G (rs4986992) (synonymous), 402T > C (rs146727732) (synonymous), 445G > A (rs4987076) (V149I), 613A > G (rs72554609) (M205V) and 640T > G (rs4986783) (S241A) did not significantly affect Vmax for ABP N-acetyltransferase or N-OH-ABP O-acetyltransferase. 781G > A (rs72554610) (E261K), and 787A > G (rs72554611) (I263V) slightly reduced ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activities whereas 560G > A (rs4986782) (R187Q) substantially and significantly reduced them. 560G > A (rs4986782) (R187Q) significantly reduced the apparent Km for ABP and N-OH-ABP a finding that was not observed with any of the other NAT1 SNPs tested. These findings suggest that the role of the 560G > A (rs4986782) (R187Q) SNP cancer risk assessment may be modified by exposure level to aromatic amine carcinogens such as ABP.
人类芳基胺N - 乙酰基转移酶1（NAT1）催化芳基胺致癌物如4 - 氨基联苯（ABP）的N - 乙酰化反应，并且在N - 羟基化之后，催化N - 羟基 - 芳基胺致癌物如N - 羟基 - ABP（N - OH - ABP）的O - 乙酰化反应。NAT1基因多态性与接触后的癌症易感性相关。在将人类NAT1转染到COS - 1细胞（SV40转化的非洲绿猴肾细胞）后，评估了NAT1编码外显子中各个单核苷酸多态性（SNP）对米氏动力学常数的影响，以检测ABP N - 乙酰基转移酶和N - OH - ABP O - 乙酰基转移酶活性。NAT1编码区SNP 97C>T（rs56318881）（R33stop）、190C>T（rs56379106）（R64W）、559C>T（rs5030839）（R187stop）和752A>T（rs56172717）（D251V）使ABP N - 乙酰基转移酶和N - OH - ABP O - 乙酰基转移酶活性降低至检测限以下。21T>G（rs4986992）（同义突变）、402T>C（rs146727732）（同义突变）、445G>A（rs4987076）（V149I）、613A>G（rs72554609）（M205V）和640T>G（rs4986783）（S241A）对ABP N - 乙酰基转移酶或N - OH - ABP O - 乙酰基转移酶的Vmax没有显著影响。781G>A（rs72554610）（E261K）和787A>G（rs72554611）（I263V）略微降低了ABP N - 乙酰基转移酶和N - OH - ABP O - 乙酰基转移酶活性，而560G>A（rs4986782）（R187Q）则大幅且显著地降低了它们的活性。560G>A（rs4986782）（R187Q）显著降低了ABP和N - OH - ABP的表观Km，这一结果在测试的其他任何NAT1 SNP中均未观察到。这些发现表明，560G>A（rs4986782）（R187Q）SNP在癌症风险评估中的作用可能会因接触芳香胺致癌物如ABP的水平而改变。
