Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine riddelliine

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Title:	Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine riddelliine
Authors:	Ming W. Chou;Yu-Ping Wang;Jian Yan;Ya-Chen Yang;Richard Beger;Lee D.Williams;Daniel R. Doerge;Peter P. Fu
Contributors:	保健營養生技學系
Keywords:	Riddelliine N-oxide;Riddelliine;Pyrrolizidine alkaloid;DHP-derived DNA adducts;32P-Postlabeling/HPLC analysis
Date:	2003
Issue Date:	2009-10-28 09:25:25 (UTC+0)
Abstract:	Pyrrolizidine alkaloids (PAs) and their N-oxide derivatives are naturally-formed genotoxic phytochemicals that are widely distributed throughout the world. Although, the quantities of PAs and PA N-oxides in plants are nearly equal, the biological and genotoxic activities of PA N-oxides have not been studied extensively. PA N-oxides are major metabolites of PAs and are generally regarded as detoxification products. However, in this study, we report that rat liver microsomes converted riddelliine N-oxide to the genotoxic 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) metabolite. Metabolism of riddelliine N-oxide by rat liver microsomes under hypoxic conditions (argon) generated predominantly the parent PA, riddelliine. The reduction of riddelliine N-oxide to riddelliine was diminished, when the metabolism of riddelliine N-oxide with rat liver microsomes was conducted aerobically. Rat liver microsomal incubations of riddelliine N-oxide in the presence of calf thymus DNA produced a set of DHP-derived DNA adducts as detected and quantified by 32P-postlabeling/HPLC. The same DHP-derived DNA adducts were also found in liver DNA of F344 rats fed riddelliine N-oxide or riddelliine. When rats received doses of 1.0 mg/kg riddelliine N-oxide for three consecutive days, the level of DNA adducts was 39.9±0.6 adducts/107 nucleotides, which was 2.6-fold less than that measured in rats treated with riddelliine at the same dose. We have previously shown that these DHP-derived DNA adducts are produced by chronic feeding of riddelliine and that the adduct levels correlated with liver tumor formation. Results presented in this paper indicate that riddelliine N-oxide, through its conversion to riddelliine, is also a potential genotoxic hepatocarcinogen.
Relation:	Toxicology Letters, 145(3):239-247.
Appears in Collections:	[Department of Food Nutrition and Healthy Biotechnology] Journal Article

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