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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

1


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


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


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


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


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

1


Simulating of in vivo detoxification

  • simulating in vivo detoxification

  • simulating in vivo bio-exhausting

1


Simulating of in vivo detoxification

  • simulating in vivo detoxification

  • simulating in vivo bio-exhausting

1


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).

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In vivo Detoxification of Styrene

(in vivo metabolism)

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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


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


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).

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Simulating in vivo detoxification of styrene by TIMES

1


1


“Trapped” reactive metabolites in in vivo detoxification

Pathway I

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“Trapped” reactive metabolites in in vivo detoxification

Pathway II

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Simulating of in vivo detoxification

  • simulating in vivo detoxification

  • simulating in vivo bio-exhausting

1


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

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Negative in vivo GT (MNT) effect of Nitrobenzene

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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

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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


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

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