The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice

Lin Zhu, Junyi Xue, Qingsu Xia, Peter P. Fu*, Ge Lin*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)949-965
Number of pages17
JournalArchives of Toxicology
Volume91
Issue number2
Early online date28 Apr 2016
DOIs
Publication statusPublished - Feb 2017

Scopus Subject Areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

User-Defined Keywords

  • Biomarker
  • DNA adducts
  • Kinetics
  • Pyrrolizidine alkaloid

Fingerprint

Dive into the research topics of 'The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice'. Together they form a unique fingerprint.

Cite this