期刊
ARCHIVES OF TOXICOLOGY
卷 91, 期 2, 页码 949-965出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-016-1713-z
关键词
Pyrrolizidine alkaloid; DNA adducts; Biomarker; Kinetics
类别
资金
- Research Grant Council of Hong Kong (GRF Grant) [471310, 469712]
- CUHK [4054047, 4054134]
- CUHK One-off Funding for Joint Lab/Research Collaboration [3132968]
- CUHK School of Biomedical Sciences-Seed Fund for Joint Establishments
Pyrrolizidine alkaloid (PA)-containing plants are widespread in the world and the most common poisonous plants affecting livestock, wildlife, and humans. Our previous studies demonstrated that PA-derived DNA adducts can potentially be a common biological biomarker of PA-induced liver tumor formation. In order to validate the use of these PA-derived DNA adducts as a biomarker, it is necessary to understand the basic kinetics of the PA-derived DNA adducts formed in vivo. In this study, we studied the dose-dependent response and kinetics of PA-derived DNA adduct formation and removal in male ICR mice orally administered with a single dose (40 mg/kg) or multiple doses (10 mg/kg/day) of retrorsine, a representative carcinogenic PA. In the single-dose exposure, the PA-derived DNA adducts exhibited dose-dependent linearity and persisted for up to 4 weeks. The removal of the adducts following a single-dose exposure to retrorsine was biphasic with half-lives of 9 h (t (1/2 alpha)) and 301 h (similar to 12.5 days, t (1/2 beta)). In the 8-week multiple exposure study, a marked accumulation of PA-derived DNA adducts without attaining a steady state was observed. The removal of adducts after the multiple exposure also demonstrated a biphasic pattern but with much extended half-lives of 176 h (similar to 7.33 days, t (1/2 alpha)) and 1736 h (similar to 72.3 days, t (1/2 beta)). The lifetime of PA-derived DNA adducts was more than 8 weeks following the multiple-dose treatment. The significant persistence of PA-derived DNA adducts in vivo supports their role in serving as a biomarker of PA exposure.
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