title: The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice.
abstract: 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 (t1/2α) and 301 h (~12.5 days, t1/2β). 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 (~7.33 days, t1/2α) and 1736 h (~72.3 days, t1/2β). 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.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.|Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.|Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Xue
authors.affiliation: National Center for Toxicological Research, Jefferson, AR, 72079, USA.
authors.forename: Qingsu
authors.initials: Q
authors.lastname: Xia
authors.affiliation: National Center for Toxicological Research, Jefferson, AR, 72079, USA. peter.fu@fda.hhs.gov.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Fu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. linge@cuhk.edu.hk.|Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. linge@cuhk.edu.hk.
authors.forename: Ge
authors.initials: G
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018736:DNA Adducts / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D011763:Pyrrolizidine Alkaloids / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D018736:DNA Adducts; D011763:Pyrrolizidine Alkaloids; C003300:retrorsine
keywords: Biomarker; DNA adducts; Kinetics; Pyrrolizidine alkaloid