Lack of Apparent Base Sequence Preference of Activated Pyrrolizidine Alkaloid Cross- Links with DNA
Contribution to Book
Poisonous Plants and Related Toxins
T. Acamovic, C.S. Stewart and T.W. Pennycott
Upon ingestion, pyrrolizidine alkaloids (PAs) are oxidized by cytochromes P-450 (CYPs) to reactive, pyrrolic bifunctional electrophiles that readily cross-link DNA, a reputed event critical in PA-induced toxicity. Our laboratory has demonstrated that PAs from nearly equal proportions of both DNA interstrand and DNA-protein cross-links in vitro (Hincks et al., 1991), and that the cytotoxic, antimitotic and megalocytic activity of PAs correlate with cross-linking (Kim et al. 1993)... We have recently shown that actin is the major protein involved in cellular PA-induced DNA-protein cross-links (Coulombe et al., 1999). Dehydrosenecionine (DHSN) and dehydromonocrotaline (DHMO) have also been shown to inhibit amplification fo a segment of pBR322, implying that cross-linking by activated PAs is functionally significant (Kim et al., 1999).
Coulombe, R.A., and W. K. Rieben (2003). Lack of Apparent Base Sequence Preference of Activated Pyrrolizidine Alkaloid Cross-Links with DNA, in Poisonous Plants and Related Toxins, (T. Acamovic, C.S. Stewart and T.W. Pennycott eds.) CAB International, London. pp. 26-31.