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, 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.
Pereira
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TN
National Research Centre for Environmental Toxicology, 39 Kessels Road, Coopers Plains, QLD 4108, Australia.
Webb
R I
RI
Reilly
P E
PE
Seawright
A A
AA
Prakash
A S
AS
D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation / Q000187:drug effects; D000818:Animals; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D018983:DNA Footprinting; D053938:DNA Fragmentation / Q000187:drug effects* / Q000235:genetics; D006147:Guanine / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008956:Models, Chemical; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000494:pharmacology; D016296:Mutagenesis; D010957:Plasmids / Q000235:genetics / Q000648:ultrastructure
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; C014114:monocrotaline pyrrole; D006147:Guanine; D016686:Monocrotaline