Chapter 6: Bioactivation of Natural Products and Biological Assay of Carcinogens

In addition to bioavailability and selective toxicity (discussed in Chapter 3), many natural products are metabolised by enzymes produced by the host. One particular class of enzymes is cytochrome P450s (commonly abbreviated to CYPs). This can lead to the bioactivation of compounds which in turn has a significant effect on their biological profile. The examples of alkaloids in general and pyrrolizidine alkaloids in particular are considered in this chapter. One particular aspect of the toxicity of pyrrolizidine alkaloids is their association with hepatocellular carcinomas. While binding to DNA is a key step for genotoxic carcinogens, a number of other factors (particularly the site of reaction, subsequent DNA repair and the conversion to a biologically significant mutation) are also important. The impact of activated pyrrolizidine alkaloids on a specific part of a tumour suppressor gene (p53) is examined. This specific example leads to a discussion of agency and passivity of natural products in nature, the concept of vitalism and the importance of empiricism and reductionism in defining the specificity of the mode of action of natural products on living systems.