The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice.
Arch Toxicol
; 91(2): 949-965, 2017 Feb.
Article
em En
| MEDLINE
| ID: mdl-27125825
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 (t 1/2α) and 301 h (~12.5 days, t 1/2ß). 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, t 1/2α) and 1736 h (~72.3 days, t 1/2ß). 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Alcaloides de Pirrolizidina
/
Adutos de DNA
Limite:
Animals
Idioma:
En
Revista:
Arch Toxicol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China