Abstract
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.
Highlights
Human occupational exposures to 4-aminobiphenyl (ABP) led to excess incidence of urinary bladder cancer with sufficient evidence for listing as a Group 1 carcinogen (IARC, 1987)
Arylamine carcinogens such as ABP are N-hydroxylated by cytochrome P450 to N-hydroxy-ABP (N-OH-ABP) followed by O-acetylation catalyzed by arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) to N-acetoxy-ABP which is highly unstable resulting in DNA adducts
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 catalyzed by recombinant human NAT1 expressed in COS-1 cells
Summary
Human occupational exposures to 4-aminobiphenyl (ABP) led to excess incidence of urinary bladder cancer with sufficient evidence for listing as a Group 1 carcinogen (IARC, 1987). Subsequent human epidemiological investigations have focused on the elevated cancer incidence in cigarette smokers, in the urinary bladder (NTP, 2021). In addition to both mainstream and sidestream cigarette smoke, ABP is a byproduct in the synthesis of numerous chemicals and color additives (NTP, 2021). DNA adducts following exposure to ABP serve as a biomarker of internal exposure and possibly carcinogenesis in human tissues (NTP, 2021). Arylamine carcinogens such as ABP are N-hydroxylated by cytochrome P450 to N-hydroxy-ABP (N-OH-ABP) followed by O-acetylation catalyzed by arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) to N-acetoxy-ABP which is highly unstable resulting in DNA adducts. NAT1 catalyzes ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activities (Hein et al, 1993; Millner et al, 2012; Zhou et al, 2013; Leggett et al, 2021; Leggett et al, 2022; Hein et al, 2022)
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