1. Mechanisms of Toxicity
Chapter 3
Mechanisms of Toxicity
Toxicology - Chaper 4
卫生毒理学

2. 卫生毒理学

3. Delivery: from the site of exposure to the target
Section 1
Delivery: from the site of exposure to the target
Toxicology - Chaper 4

4. Absorption versus Presystemic Elimilation
Absorption: Transfer of a chemical from the site of exposure into the systemic circulation
Presystemic Elimilation: The GI mucosa and the liver may elimilate a significant fraction of a txicant during its passage through tissues, decreasing its systemic availability
Toxicology - Chaper 4
卫生毒理学

5. Distribution to and away from the target
Mechanisms facilitating distribution to a target:
Porosity of the capillary endothelium
Specialized membrane transport
Reversible intracellular binding
Toxicology - Chaper 4
卫生毒理学

6. Distribution to and away from the target
Mechanisms opposing distribution to a target:
Binding to plasma proteins
Specialized barriers
Distribution to storage sites
Export from cells
Toxicology - Chaper 4
卫生毒理学

7. Excretion versus Reabsorption
Excretion: Physical removal of xenobiotics from the blood and their return to the external environment
Reabsorption: Diffusion of toxicants in the renal tubules and the GI tract across the tubular cells and intestinal mucosa back into the circulation
Toxicology - Chaper 4
卫生毒理学

8. Toxication versus Detoxication
Toxication: Biotransformation of xenobiotics to harmful products, also called activation
Toxicology - Chaper 4
卫生毒理学

9. Toxication versus Detoxication
The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics.
This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds.
Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa.
Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities.
Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved.
Toxicology - Chaper 4

10. Toxicology - Chaper 4

11. Toxication versus Detoxication
Toxication: Biotransformation of xenobiotics to harmful products, also called activation
Formation of electrophiles
Formation of free radicals
Formation of nucleophiles
Formation of redox-active reactants
Toxicology - Chaper 4
卫生毒理学

13. Toxication versus Detoxication
Detoxication: Biotransformation which eliminate the ultimate toxicant or prevent its formation
Detoxication of toxicants with no functional groups
Detoxication of electrophiles
Detoxication of free radicals
Detoxication of nucleophiles
Detoxication of protein toxins
Toxicology - Chaper 4
卫生毒理学

14. Toxicology - Chaper 4

15. Toxication versus Detoxication
When detoxication fails
Exhaustion of the detoxication enzymes
Consumption of cosubstrates
Depletion of cellular antioxidants
Conjugation reaction reversed
Generation of harmful by-products
Toxicology - Chaper 4
卫生毒理学

16. 卫生毒理学

17. Some important terms
Some important terms that are often used when discussing activation
include parent compound, sometimes referred to as procarcinogen in the case of a carcinogen or prodrug for pharmaceutical compounds;
proximate toxic metabolite or proximate carcinogen for one or more of the intermediates; and ultimate toxic metabolite or ultimate carcinogen for the reactive species that binds to macromolecules and DNA.
Toxicology - Chaper 4

18. The relationship between metabolism, activation, detoxication, and toxicity of a chemical.

19. Reaction of the ultimate toxicant with the target molecule
Section 2
Reaction of the ultimate toxicant with the target molecule
Toxicology - Chaper 4

20. Types of Reaction Noncovalent binding covalent binding
Hydrogen abstraction
Electron transfer
Enzymatic reactions
Toxicology - Chaper 4
卫生毒理学

21. Effects of Toxicants on Target Molecules
Attributes of target molecules
Dysfunction of target molecules
Destruction of target molecules
Neoantigen formation
Toxicology - Chaper 4
卫生毒理学

22. Toxicology - Chaper 4

23. Toxicology - Chaper 4

24. Cellular Dysfunction and Resultant Toxicities
Section 3
Cellular Dysfunction and Resultant Toxicities
Toxicology - Chaper 4

25. Toxicant-induced Cellular Dysregulation
Dysregulation of gene expression
Dysregulation of transcription
Dysregulation of signal transduction
Dysregulation of signal production
Dysregulation of ongoing cellular activity
Dysregulation of electrically excitable and nonexcitable cells
Toxicology - Chaper 4
卫生毒理学

26. Toxic Alteration of Cellular Maintenance
Impairment of internal cellular maintenance: mechanisms of toxic cell death
Impaired ATP synthesis
Sustained rise of intracellular Ca++
Damage of plasma membrane, lysosome, cytoskeleton, protein synthesis
Impairment of External cellular maintenance
Interruption of hepatic function
Toxicology - Chaper 4
卫生毒理学

27. Toxicology - Chaper 4

28. Section 4
Repair or Dysrepair
Toxicology - Chaper 4

29. Toxicology - Chaper 4

30. Molecular Repair Repair of proteins: enzymatic reduction
Repair of lipids: reductants and reductase
Repair of DNA
Direct repair
Excision repair
Recombinational (or postreplication) repair
Toxicology - Chaper 4
卫生毒理学

31. Cellular Repair
In most cases injured cells die with the survivors dividing to replace the lost cells
An exception: nerve tissues
A strategy in peripheral neurons
Axonal damage repairs require macrophages and Schwann cells (NGF)
Toxicology - Chaper 4
卫生毒理学

32. Tissue Repair Apoptosis: an active deletion of damaged cells
Proliferation: regeneration of tissue
Replacement of lost cells by mitosis
Replacement of extracellular matrix
Toxicology - Chaper 4
卫生毒理学

34. Tissue Repair Side reactions to tissue injury Inflammation
Altered protein synthesis: acute-phase proteins (C-reactive protein, fibrinogen)
Generalized reactions: increased release of cytokines (IL-1, IL-6, TNF)
Toxicology - Chaper 4
卫生毒理学

35. Toxicity Resulting from Dysrepair
Tissue necrosis
Fibrosis
Carcinogenesis
Toxicology - Chaper 4
卫生毒理学

36. Carcinogenesis
Failure of DNA repair: mutation, the initiating event in carcinogenesis
Failure of apoptosis: promotion of mutation and clonal growth
Failure to terminate proliferation: promotion of mutation, proto-oncogene expression, and clonal growth
Nongenotoxic carcinogens: promoters of mitosis and inhibitors of apoptosis
Toxicology - Chaper 4
卫生毒理学

37. More mechanisms of toxicity are waiting for your explosion
Toxicology - Chaper 4
卫生毒理学