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Simulating of in vivo metabolism taking into account detoxification logics

Simulating of in vivo metabolism taking into account detoxification logics. Levels of GT Investigation. in vitro Genotoxicity. in vivo Genotoxicity. Blood Transport. AMES CA. Liver. Bone Marrow. in vivo bio-exhausting. Activation (Phase I) Conjugation (Phase II)

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Simulating of in vivo metabolism taking into account detoxification logics

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  1. Simulating of in vivo metabolism taking into account detoxification logics 1

  2. Levels of GT Investigation in vitro Genotoxicity in vivo Genotoxicity Blood Transport AMES CA Liver Bone Marrow in vivo bio-exhausting Activation (Phase I) Conjugation (Phase II) DNA/Protein reactivity no pharmacokinetics factors Activation (Phase I) Conjugation (Phase II) DNA/Protein reactivity pharmacokinetics factors in vivo detoxification “logic” Effect 1

  3. Levels of GT Investigation: First-Pass Metabolism? Level III Level I Level II in vitro mutagenicity in vivo liver genotoxicity in vivo MN genotoxicity negative negative negative chemical negative negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive positive 1

  4. Levels of GT Investigation: First-Pass Metabolism? Level III Level I Level II in vitro mutagenicity in vivo liver genotoxicity in vivo MN genotoxicity negative negative negative negative negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive positive 1

  5. Levels of GT Investigation: First-Pass Metabolism? Level III Level I Level II in vitro mutagenicity in vivo liver genotoxicity in vivo MN genotoxicity negative negative negative negative negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive positive 1

  6. Simulating of in vivo metabolism taking into account detoxification and bio-exhausting 1

  7. Simulating of in vivo detoxification • simulating in vivo detoxification • simulating in vivo bio-exhausting 1

  8. Simulating of in vivo detoxification • simulating in vivo detoxification • simulating in vivo bio-exhausting 1

  9. In vivo Detoxification Includes: • Principal phase II metabolic detoxification reactions: • glutathione conjugation • glucuronidation • amino acid conjugation • acetylation • sulfation • Detoxification “logic” (Complete metabolic detoxification suppresses genotoxic action of reactive intermediates in liver). 1

  10. In vivo Detoxification of Styrene (in vivo metabolism) 1

  11. Observed in vitro metabolic pathway for styrene R=Aryl In vitro genotoxic effects of styrene epoxide DNA reactivity observed in vitro Protein binding observed in vitro Styrene oxide is hydrolyzed in vitro to styrene glycol by microsomal epoxide hydrolase from the liver, kidneys, intestine, lungs, and skin of several mammalian species (Oesch 1973, cited in IARC 1985). 1

  12. Observed in vivo MNT metabolic pathway for styrene R=Aryl “Trapped” metabolite due to the “channeling” effect DNA reactivity observed in vitro Protein binding observed in vitro Mutagenic effects of styrene in vivo can be expected under extreme exposure conditions if styrene oxide is not efficiently detoxified and primary DNA lesions are not completely repaired. (Speit et al. 2008). 1

  13. Observed in vivo MNT metabolic pathway for styrene R=Aryl “Trapped” metabolite due to the “channeling” effect DNA reactivity observed in vitro Protein binding observed in vitro A recent published data for in vivo MNT in bone marrow cells of mice was clearly negative (Speit et al. 2008). 1

  14. Simulating in vivo detoxification of styrene by TIMES 1

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  16. “Trapped” reactive metabolites in in vivo detoxification Pathway I 1

  17. “Trapped” reactive metabolites in in vivo detoxification Pathway II 1

  18. Simulating of in vivo detoxification • simulating in vivo detoxification • simulating in vivo bio-exhausting 1

  19. Bio-exhausting Detoxification Scenarios: • The in vivo bio-exhausting detoxification scenarios include: • highly reactive metabolites of liver GT chemicals are bio-exhausted approaching to the MN bone marrow due to off-target reactions, therefore, they becomeincapable of producing harmful effects on the target tissue (bone marrow). • bio-exhausting of short – lived intermediates formed in liver 1

  20. Negative in vivo GT (MNT) effect of Nitrobenzene 1

  21. Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway I Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow 1

  22. Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway II Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow 1

  23. Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway III Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow 1

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