Abstract
We have previously shown that riddelliine, a naturally occurring genotoxic pyrrolizidine alkaloid, induces liver tumors in rats and mice through a genotoxic mechanism mediated by the formation of a set of eight 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine ( DHP)-derived DNA adducts. In this study we report the formation of these DHP-derived DNA adducts in blood DNA of rats fed riddelliine. In an adduct formation and removal experiment, male and female F344 rats (8 weeks of age) were administered riddelliine by gavage at a single dose of 10.0 mg/kg body weight in 0.1 M phosphate buffer. At 8, 24, 48, and 168 hrs after dosing, the levels of DHP-derived DNA adduct in blood and liver were determined by 32P-postlabeling/HPLC. Maximum DNA adduct formation occurred at 48 hr after treatment. From 48 to 168 hours, the adduct levels in female rat blood were 4-fold greater than those in male rats. In a dose response experiment, female rats were gavaged 0.1 and 1.0 mg/kg doses of riddelliine for three consecutive days and the DHPderived DNA adducts in blood DNA were assayed. The levels of the DHP-derived DNA adducts in blood of rats receiving 0.1 and 1.0 mg/kg doses were 12.9 and 51.8 adducts/107 nucleotides. These results suggest that: (i) leucocyte DNA can bind with DHP to form a set of DHP-derived DNA adducts generated in liver; (ii) DHP-derived DNA adducts in blood can serve as a potential non-invasive biomarkers for assessing the exposure to riddelliine.
Highlights
Riddelliine is a naturally occurring genotoxic pyrrolizidine alkaloid, consisting of a riddelliic acid and a retronecine base (Scheme 1), and is widespread in rangelands of the western United States [1,2,3]
Our results showed that leucocyte DNA can bind with DHP to form the DHP-derived DNA adducts similar as those generated in liver, at a lower level
The necine-based carcinogenic pyrrolizidine alkaloids, such as riddelliine, are metabolized to form reactive pyrrolic metabolites that can bind to the cellular macromolecules, such as proteins and DNA
Summary
Riddelliine is a naturally occurring genotoxic pyrrolizidine alkaloid, consisting of a riddelliic acid and a retronecine base (Scheme 1), and is widespread in rangelands of the western United States [1,2,3]. Livestock have been poisoned by ingesting plants containing toxic pyrrolizidine alkaloids, including riddelliine, and resulted in tremendous economic loss [8]. By 32P-postlabeling/ HPLC analysis, a set of eight DHP-derived DNA adducts was detected both in vitro and in vivo [7,11]. These DHP-derived DNA adducts consist of a pair of epimeric DHP-3 ́-dGMP adducts and six DHP-derived deoxyribodinucleotides [16]. The level of the total DHP-derived DNA adducts in liver DNA of rats fed riddelliine was dose- and time-dependent [11]
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