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Hodgson E. Modern toxicology [2004].pdf
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268 HEPATOTOXICITY

Sites of blocking oxidant challenges by antioxidant defenses.

electron transport proteins

activated phagocytes nitric oxide synthetase redox cycling

GSH redox

SOD

 

 

 

 

O2

 

 

 

 

NO

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H2O2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

cycle; catalase

 

 

 

 

 

 

 

 

 

 

 

 

 

metal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ions

 

 

 

OONO/

NOx

 

 

 

HOO

 

 

 

 

HO

 

 

 

 

 

HOONO

 

 

 

 

 

 

 

 

 

 

 

 

 

 

biomolecules (DNA, lipid, protein)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RO

 

 

 

 

 

 

 

 

biomolecule radicals

 

 

 

 

 

 

 

 

 

 

 

 

 

metal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O2

 

 

 

ions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

chain-breaking

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ROO

 

 

 

ROOH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

antioxidants

 

 

 

 

 

 

 

 

 

GSH redox

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

cycle

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

propagation of oxidative damage

Figure 14.2 Molecular targets of oxidative injury. (From D. J., Reed,Introduction to Biochemical Toxicology, 3rd ed., Wiley, 2001.)

2-naphthylamineand acetylaminofluorene, and vinyl chloride. The structure and activation of these compounds can be found in Chapters 7 and 8. In humans, the most noted case ofoccupation-relatedliver cancer is the development of angiosarcoma, a rare malignancy of blood vessels, among workers exposed to high levels of vinyl chloride in manufacturing plants. For a discussion of chemical carcinogenesis, see Chapter 12.

14.4MECHANISMS OF HEPATOTOXICITY

Chemically induced cell injury can be thought of as involving a series of events occurring in the affected animal and often in the target organ itself:

žThe chemical agent is activated to form the initiating toxic agent.

žThe initiating toxic agent is either detoxified or causes molecular changes in the cell.

žThe cell recovers or there are irreversible changes.

žIrreversible changes may culminate in cell death.