Title

Pyrrolizidine Alkaloid-Induced DNA-Protein Cross-Links

Document Type

Article

Journal/Book Title/Conference

Carcinogenesis

Volume

16

Issue

11

Publisher

Oxford University Press

Publication Date

1995

First Page

2691

Last Page

2697

Abstract

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 µM, the pyrrolic PAs (dehydrosenecionine, dehydromonocrotaline, dehydroseneciphylline, dehydroriddelliine) induced potent DNA cross-links. Protein-associated DNA cross-links accounted for ~50% of the total cellular DNA cross-links at 300 µM. 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, cis-dichlorodiammine 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 diseases.

Comments

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