Dehydromonocrotaline generates sequence-selective N-7 guanine alkylation and heat and alkali stable multiple fragment DNA crosslinks

Monocrotaline is a pyrrolizidine alkaloid known to cause toxicity in humans and animals. Its mechanism of biological action is still unclear although DNA crosslinking has been suggested to a play a role in its activity. In this study we found that an active metabolite of monocrotaline, dehydromonocr...

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Bibliographic Details
Published in:Nucleic acids research 1998-12, Vol.26 (23), p.5441-5447
Main Authors: Pereira, T.N, Webb, R.I, Reilly, P.E.B, Seawright, A.A, Prakash, A.S
Format: Article
Language:English
Subjects:
Alkylating Agents - pharmacology
alkylation
Alkylation - drug effects
Animals
Cross-Linking Reagents - pharmacology
DNA Adducts - chemistry
DNA Adducts - metabolism
DNA Adducts - ultrastructure
dna crosslinking
DNA Footprinting
DNA Fragmentation - drug effects
DNA Fragmentation - genetics
dna modification
genotoxicity
guanine
Guanine - metabolism
Hot Temperature
Humans
metabolites
Models, Chemical
Monocrotaline - analogs & derivatives
Monocrotaline - pharmacology
Mutagenesis
nucleotide sequences
Plasmids - genetics
Plasmids - ultrastructure
pyrrolizidine alkaloids
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Summary:Monocrotaline is a pyrrolizidine alkaloid known to cause toxicity in humans and animals. Its mechanism of biological action is still unclear although DNA crosslinking has been suggested to a play a role in its activity. In this study we found that an active metabolite of monocrotaline, dehydromonocrotaline (DHM), alkylates guanines at the N7 position of DNA with a preference for 5′-GG and 5′-GA sequences. In addition, it generates piperidine- and heat-resistant multiple DNA crosslinks, as confirmed by electrophoresis and electron microscopy. On the basis of these findings, we propose that DHM undergoes rapid polymerization to a structure which is able to crosslink several fragments of DNA.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/26.23.5441