Mechanisms of Toxicity

Toxicology - Chaper 4 1

Mechanisms of Toxicity

Chapter 3


Delivery: from the site of exposure to the target

Section 1


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


Distribution to and away from the target

• Mechanisms facilitating distribution to a target:

– Porosity of the capillary endothelium

– Specialized membrane transport

– Reversible intracellular binding


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


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


Toxication versus Detoxication

• Toxication: Biotransformation of xenobiotics to harmful products, also called activation



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.




• 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



• 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




• When detoxication fails– Exhaustion of the detoxication enzymes– Consumption of cosubstrates– Depletion of cellular antioxidants– Conjugation reaction reversed– Generation of harmful by-products


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.

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


Reaction of the ultimate toxicant with the target

molecule

Section 2


Types of Reaction

• Noncovalent binding

• covalent binding

• Hydrogen abstraction

• Electron transfer

• Enzymatic reactions


Effects of Toxicants on Target Molecules

• Attributes of target molecules

• Dysfunction of target molecules

• Destruction of target molecules

• Neoantigen formation




Cellular Dysfunction and Resultant Toxicities

Section 3


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


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



Repair or Dysrepair

Section 4



Molecular Repair

• Repair of proteins: enzymatic reduction

• Repair of lipids: reductants and reductase

• Repair of DNA

– Direct repair

– Excision repair

– Recombinational (or postreplication) repair


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)


Tissue Repair

• Apoptosis: an active deletion of damaged cells

• Proliferation: regeneration of tissue

• Replacement of lost cells by mitosis

• Replacement of extracellular matrix


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)


Toxicity Resulting from Dysrepair

• Tissue necrosis

• Fibrosis

• Carcinogenesis


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


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