Related Experiment Videos
An overview of bioactivation of chemical carcinogens
1German Institute of Human Nutrition (DIfE), Potsdam-Rehbruecke.
Abstract:
Most environmental carcinogens require metabolic activation to reactive intermediates and are mutagenic in appropriate test systems. During the last decade, the cDNAs of numerous xenobiotic-metabolizing enzymes have been cloned. The individually expressed enzymes were used to study their substrate specificities and their inhibition by other compounds. Various enzymes were expressed directly in target cells of in vitro mutagenicity tests. This is illustrated in the present study for rat and human sulphotransferases (SULTs) expressed in Salmonella typhimurium TA1538. Numerous compounds were mutagenic in the new test system. Some of these promutagens were activated by several different SULT forms, whereas many other promutagens were activated with high selectivity by a specific enzyme form, but not by genetically closely related forms from the same species (e.g. allelic variants) or orthologous enzymes from other species. Similar findings have been made using recombinant test systems for specific forms of other classes of enzymes (e.g. cytochromes P450). This high selectivity in activation (and inactivation) may explain some organotropisms as well as species and inter-individual differences in the action of carcinogens. Many carcinogen-metabolizing enzymes are induced or inhibited by other xenobiotics. Such interactions can be exploited for chemo-prevention, which however may be carcinogen- and tissue-dependent.
Insights
Environmental carcinogens often need metabolic activation to become mutagenic. This study shows specific sulphotransferases (SULTs) selectively activate some carcinogens, explaining differences in cancer risk.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Environmental carcinogens require metabolic activation to reactive intermediates, often exhibiting mutagenicity.
- Cloning of xenobiotic-metabolizing enzyme cDNAs has enabled functional studies over the past decade.
- Recombinant expression systems allow investigation of enzyme specificities and interactions.
Purpose of the Study:
- To investigate the substrate specificity and activation capabilities of rat and human sulphotransferases (SULTs).
- To assess the mutagenicity of various compounds using SULTs expressed in Salmonella typhimurium.
- To explore the selectivity of enzyme activation and its implications for carcinogen action.
Main Methods:
- Cloning and expression of rat and human sulphotransferase (SULT) cDNAs in Salmonella typhimurium TA1538.
- In vitro mutagenicity testing of various compounds using the engineered bacterial strains.
- Comparative analysis of activation patterns across different SULT forms, species, and allelic variants.
Main Results:
- Numerous compounds demonstrated mutagenicity in the SULT-expressing Salmonella system.
- Some promutagens were activated by multiple SULT forms, while others showed high selectivity for specific SULTs.
- Activation selectivity varied significantly between closely related SULT forms and orthologous enzymes from different species.
Conclusions:
- The high selectivity of SULTs in activating (and inactivating) carcinogens can explain organotropism and species-specific differences in carcinogen effects.
- Understanding these selective activation pathways is crucial for predicting individual susceptibility to environmental carcinogens.
- Exploiting enzyme induction or inhibition offers potential for chemo-prevention strategies, though these are dependent on the specific carcinogen and tissue context.