Dose-response formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine in liver and urine correlates with micronucleated reticulocyte frequencies in mice administered safrole oxide.

Abstract

Safrole oxide (SAFO), a metabolite of naturally occurring hepatocarcinogen safrole, is implicated in causing DNA adduct formation. Our previous study first detected the most abundant SAFO-induced DNA adduct, N7-(3-benzo[1,3] dioxol-5-yl-2-hydroxypropyl)guanine (N7γ-SAFO-G), in mouse urine using a well-developed isotope-dilution high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (ID-HPLC-ESI-MS/MS) method. This study further elucidated the genotoxic mode of action of SAFO in mice treated with SAFO 30, 60, 90, or 120 mg/kg for 28 days. The ID-HPLC-ESI-MS/MS method detected N7γ-SAFO-G with excellent sensitivity and specificity in mouse liver and urine of SAFO-treated mice. Our data provide the first direct evidence of SAFO-DNA adduct formation in rodent tissues. N7γ-SAFO-G levels in liver were significantly increased by SAFO 120 mg/kg compared with SAFO 30 mg/kg, suggesting rapid spontaneous or enzymatic depurination of N7γ-SAFO-G in tissue DNA. Urinary N7γ-SAFO-G exhibited a sublinear dose response. Moreover, the micronucleated peripheral reticulocyte frequencies increased dose-dependently and significantly correlated with N7γ-SAFO-G levels in liver (r = 0.8647; p < 0.0001) and urine (r = 0.846; p < 0.0001). Our study suggests that safrole-mediated genotoxicity may be caused partly by its metabolic activation to SAFO and that urinary N7γ-SAFO-G may serve as a chemically-specific cancer risk biomarker for safrole exposure.

• Authors: Kuen-Yuh Wu, Yu-Tzu Wei, Yu-Syuan Luo, Li-Chin Shen, Bao-Suei Chang, Ya-Yin Chen, Yan-Chi Huang, Hui-Fen Huang, Wen-Sheng Chung, Su-Yin Chiang
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 181 Pg. 114056 (Nov 2023) ISSN: 1873-6351 [Electronic] England
• PMID: 37739051 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• DNA Adducts
• safrole oxide
• Safrole
• Guanine

Topics

• Mice
• Animals
• DNA Adducts
• Safrole (toxicity)
• Tandem Mass Spectrometry
• Spectrometry, Mass, Electrospray Ionization (methods)
• Guanine
• Reticulocytes (chemistry, metabolism)
• Liver (metabolism)
• Chromatography, High Pressure Liquid