Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo.
Monocrotaline is a representative naturally occurring genotoxic pyrrolizidine alkaloid. Metabolism of monocrotaline by liver microsomes of F344 female rats generated (+/-)6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) and monocrotaline-N-oxide as major metabolites. Metabolism in the presence of triacetyleandomycin, a P450 3A enzyme inhibitor, reduced the formation of DHP by 52% and monocrotaline N-oxide formation by 59%. Dexamethasone significantly induced microsomal monocrotaline metabolizing enzyme activities in rat liver and lung. Previously, we have identified a set of DHP-derived DNA adducts from DHP-modified calf thymus DNA by (32)P-post labeling/HPLC analysis. Metabolism of monocrotaline in the presence of calf thymus DNA resulted in a similar set of DHP-DNA adducts. These DHP-DNA adducts were also found in the liver DNA of rats treated with monocrotaline. The time course of the DHP-derived DNA adduct formation and removal in the liver of rats gavaged with a single dose (10mg/kg) of monocrotaline was similar to that of rats treated with riddelliine. The levels of DHP-DNA adducts in liver DNA of rats treated with monocrotaline were much lower than that of riddelliine-treated rats. Results from this study indicate that (i) DHP is a common reactive metabolite for retronecine-type of pyrrolizidine alkaloids, (ii) the formation of DHP-derived DNA adducts in the liver DNA of rats treated with monocrotaline suggests that monocrotaline-induced tumorigenicity is through a genotoxic mechanism.
Wang
Yu-Ping
YP
Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA.
Yan
Jian
J
Beger
Richard D
RD
Fu
Peter P
PP
Chou
Ming W
MW
D000818:Animals; D018736:DNA Adducts; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D008099:Liver; D016686:Monocrotaline / Q000378:metabolism* / Q000633:toxicity*; D009369:Neoplasms / Q000139:chemically induced; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
C105562:2,6-dimethyl-3,5-diethoxycarbonyl-4-carboxyl-1,4-dihydropyridine; D018736:DNA Adducts; D011763:Pyrrolizidine Alkaloids; C013672:riddelliine; D003997:Dicarbethoxydihydrocollidine; D016686:Monocrotaline