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Enzyme systems involved in the control of mutagenically active metabolism products of various polycyclic hydrocarbons
153 2 Wiebel, F.J., Abteilung fiir Toxikologie, Gesellschaft fiir Strahlen- und Umweltforschung, D-8042 Neuherberg-Munich (West-Germany)
Xenobiotic-metabolizing enzymes in in vitro test systems for chemical mutagenicity This presentation concerns the role of xenobiotic-metabolizing enzymes in 2 test systems for chemical mutagenicity, the bacterial "Ames" system and mammalian cells in culture. In the bacterial systems the activation of test compounds is favored by addition of "$9" or microsomal preparations that contain the essential activating functions, i.e. the various forms of monooxygenases, but do not express many of the inactivating functions. Although modification of the various metabolic pathways may provide some insight into the mechanism and site of activation, these test systems are of limited value in estimating the mutagenic potency of chemicals. For this task mammalian cells in culture may offer a more suitable system. Recent observations indicate that established cells in culture may express monooxygenase activities that have previously been thought to be missing. Furthermore, cell lines have been found to differ greatly in their levels of inactivating enzymes. In the future, cell lines that are defined in their pattern of xenobiotic-metabolizing enzymes and are sensitive indicators of mutagenicity, may be obtained by selection or cell hybridization and aid in testing for the mutagenic potential and potency of chemicals.
3 Oesch, F., Pharmakologisches Institut, Universit~it Mainz, D-6500 Mainz (West-Germany)
Enzyme systems involved in the control of mutagenically active metabolism products of various polycyclic hydrocarbons Mammalian enzymes can metabolise non-mutagenic substances to mutagenic products. Differences in activities and patterns of activating and inactivating enzymes lead to differences between test systems and various biological situations, and between animal species, strains, sexes, developmental phases, organs and physiological conditions. Many enzymes are involved in the metabolism of various structural elements, which leads to complexity. Substances consisting exclusively of one structural element were therefore examined: polycyclic aromatic hydrocarbons. Various monooxygenases attack these hydrocarbons preferentially at different sites, which leads to patterns of primary metabolites which differ with regard to mutagenic potency, chemical stability and efficiency with which they are further metabolized. Other enzymes can further convert primary metabolites: epoxides are hydrated and conjugated with glutathione. Phenols are also conjugated. Both primary and secondary metabolites can be further oxidized by monooxygenases. This leads, among other products, to highly mutagenic dihydrodiolbay-region epoxides. By interception of the precursor, dihydrodiol dehydrogenase can reduce the formation of such metabolites.
Xenobiotic-metabolizing enzymes in in vitro test systems for chemical mutagenicity This presentation concerns the role of xenobiotic-metabolizing enzymes in 2 test systems for chemical mutagenicity, the bacterial "Ames" system and mammalian cells in culture. In the bacterial systems the activation of test compounds is favored by addition of "$9" or microsomal preparations that contain the essential activating functions, i.e. the various forms of monooxygenases, but do not express many of the inactivating functions. Although modification of the various metabolic pathways may provide some insight into the mechanism and site of activation, these test systems are of limited value in estimating the mutagenic potency of chemicals. For this task mammalian cells in culture may offer a more suitable system. Recent observations indicate that established cells in culture may express monooxygenase activities that have previously been thought to be missing. Furthermore, cell lines have been found to differ greatly in their levels of inactivating enzymes. In the future, cell lines that are defined in their pattern of xenobiotic-metabolizing enzymes and are sensitive indicators of mutagenicity, may be obtained by selection or cell hybridization and aid in testing for the mutagenic potential and potency of chemicals.
3 Oesch, F., Pharmakologisches Institut, Universit~it Mainz, D-6500 Mainz (West-Germany)
Enzyme systems involved in the control of mutagenically active metabolism products of various polycyclic hydrocarbons Mammalian enzymes can metabolise non-mutagenic substances to mutagenic products. Differences in activities and patterns of activating and inactivating enzymes lead to differences between test systems and various biological situations, and between animal species, strains, sexes, developmental phases, organs and physiological conditions. Many enzymes are involved in the metabolism of various structural elements, which leads to complexity. Substances consisting exclusively of one structural element were therefore examined: polycyclic aromatic hydrocarbons. Various monooxygenases attack these hydrocarbons preferentially at different sites, which leads to patterns of primary metabolites which differ with regard to mutagenic potency, chemical stability and efficiency with which they are further metabolized. Other enzymes can further convert primary metabolites: epoxides are hydrated and conjugated with glutathione. Phenols are also conjugated. Both primary and secondary metabolites can be further oxidized by monooxygenases. This leads, among other products, to highly mutagenic dihydrodiolbay-region epoxides. By interception of the precursor, dihydrodiol dehydrogenase can reduce the formation of such metabolites.