Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine.
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/10(7) 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.
Chou
Ming W
MW
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. mchou@nctr.fda.gov
Wang
Yu-Ping
YP
Yan
Jian
J
Yang
Ya-Chen
YC
Beger
Richard D
RD
Williams
Lee D
LD
Doerge
Daniel R
DR
Fu
Peter P
PP
D000818:Animals; D002417:Cattle; D004247:DNA / Q000187:drug effects*; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism
D018736:DNA Adducts; D009153:Mutagens; D011763:Pyrrolizidine Alkaloids; C013672:riddelliine; D016686:Monocrotaline; C068583:riddelliine N-oxide; D004247:DNA; C007241:dehydroretronecine