Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides

Xiaobo He ^a, Qingsu Xia ^a, Kellie Woodling ^a, Ge Lin ^b, Peter P. Fu ^a,*

^a National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States

^b School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

There are 660 pyrrolizidine alkaloids (PAs) and PA N-oxides present in the plants, with approximately half being possible carcinogens. We previously reported that a set of four PA-derived DNA adducts is formed in the liver of rats administered a series of hepatocarcinogenic PAs and a PA N-oxide. Based on our findings, we hypothesized that this set of DNA adducts is a common biological biomarker of PA-induced liver tumor formation. In this study, we determined that rat liver microsomal metabolism of five hepatocarcinogenic PAs (lasiocarpine, retrorsine, riddelliine, monocrotaline, and heliotrine) and their corresponding PA N-oxides produced the same set of DNA adducts. Among these compounds, lasiocarpine N-oxide, retrorsine N-oxide, monocrotaline N-oxide, and heliotrine N-oxide are for first time shown to be able to produce these DNA adducts. These results further support the role of these DNA adducts as potential common biomarkers of PA-induced liver tumor initiation.

Keywords: Pyrrolizidine alkaloid, Pyrrolizidine alkaloid N-oxide, LC–ES–MS/MS, DHP–DNA adducts