Effects of dose and human N-acetyltransferase 1 genetic polymorphism in benzidine metabolism and genotoxicity.

Autor: Habil MR; Department of Pharmacology and Toxicology and Brown Cancer Center, University of Louisville, School of Medicine, Louisville, KY, 40202, USA., Hein DW; Department of Pharmacology and Toxicology and Brown Cancer Center, University of Louisville, School of Medicine, Louisville, KY, 40202, USA. david.hein@louisville.edu.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2023 Jun; Vol. 97 (6), pp. 1765-1772. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1007/s00204-023-03497-1
Abstrakt: Benzidine undergoes N-acetylation and following CYP1A2-catalyzed N-hydroxylation undergoes O-acetylation catalyzed by N-acetyltransferase 1 (NAT1). Benzidine exposure is associated with urinary bladder cancer but the effect of NAT1 genetic polymorphism on individual risk remains unclear. We used Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and NAT1*4 allele (reference) or NAT1*14B (variant) to investigate the effects of dose and NAT1 polymorphism on benzidine metabolism and genotoxicity. Rates of benzidine N-acetylation in vitro were higher in CHO cells transfected with NAT1*4 compared to NAT1*14B. CHO cells transfected with NAT1*14B exhibited greater N-acetylation rates in situ than cells transfected with NAT1*4 at low doses of benzidine expected with environmental exposures but not at higher doses. NAT1*14B exhibited over tenfold lower apparent K M which resulted in higher intrinsic clearance for benzidine N-acetylation compared to CHO cells transfected with NAT1*4. Benzidine-induced hypoxanthine phosphoribosyl transferase (HPRT) mutations were higher in CHO cells transfected with NAT1*14B than with NAT1*4 (p < 0.001). Benzidine caused concentration-dependent increase in γ-H2AX signal (indicative of DNA double-strand breaks) in CHO cells transfected with NAT1*4 or NAT1*14B. CHO cells transfected with NAT1*14B exhibited significantly higher level of DNA damage than with NAT1*4 (p < 0.0001). Benzidine-induced ROS did not differ significantly (p > 0.05) between CHO cells transfected with NAT1*4 or NAT1*14B except at 50 μM. Levels of benzidine-induced DNA damage and reactive oxygen species (ROS) showed strong dose-dependent correlation. Our findings support human studies associating NAT1*14B with increased incidence or severity of urinary bladder cancer in workers exposed to benzidine.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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