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https://doi.org/10.1093/carcin/16.11.2691
Copy DOIJournal: Carcinogenesis | Publication Date: Jan 1, 1995 |
Citations: 81 |
Pyrrolizidine alkaloids (PAs) are potent carcinogenic and anti-mitotic compounds produced by a large number of plant species. In this study, we investigated in vitro the DNA-protein cross-linking activity of several structurally diverse PAs. The DNA cross-linked proteins induced by PAs were also isolated and characterized in mammalian cells. At 300 and 500 microM, the pyrrolic PAs (dehydrosenecionine, dehydromonocrotaline, dehydroseneciphylline, dehydroriddelliine) induced potent DNA cross-links. Protein-associated DNA cross-links accounted for approximately 50% of the total cellular DNA cross-links at 300 microM. The simple necine pyrrole dehydroretronecine induced few DNA--protein cross-links and none were detected with indicine N-oxide. The major proteins cross-linked to DNA from either PA-exposed cells or pyrrolic PA-exposed nuclei were in the molecular weight 40-60 kDa range and were primarily acidic in nature (Ca. pI 4.2-5.0). The patterns of the proteins cross-linked to DNA were similar to that induced by standard bifunctional alkylating agents mitomycin C, cisdichlorodiammine platinum(II) and nitrogen mustard. The macrocyclic pyrrole dehydrosenecionine induced DNA cross-links in pBR322 plasmid DNA with BSA as a protein target. Our data indicated that pyrrolic PAs with a macrocyclic diester such as dehydrosenecionine, dehydroseneciphylline, dehydroriddelliine and dehydromonocrotaline were more potent cross-linkers than the simple necine pyrrolic dehydroretronecine. Cross-linking potency of the PAs examined here coincides with known potency differences in animal toxicity and led us to conclude that DNA--protein cross-linking activity is probably involved in PA-related
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