Mechanisms

of Toxicity
MSc Alfredo Saracho
Agenda
• Introduction

• Step 1 – Delivery: from the Site of

Exposure to the Target

• Step 2 – Reaction of the ultimate

toxicant with the Target Molecule

• Step 3 – Cellular Dysfunction and

Resultant Toxicants

• Step 4 – Repair or Dysrepair

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Introduction Toxicity involves toxicant delivery to its target or targets and
interactions with endogenous target molecules that may
trigger perturbations in cell function and/or structure or that
may initiate repair mechanisms at the molecular, cellular,
and/or tissue levels.

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Introduction

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Key points
• Sustained elevation of intracellular Ca2+ is harmful
• Biotransformation to harmful products is called
because it can result in (1) depletion of energy reserves
toxication or metabolic activation. by inhibiting the ATPase used in oxidative
phosphorylation, (2) dysfunction of microfilaments, (3)
• Biotransformations that eliminate the ultimate
activation of hydrolytic enzymes, and (4) generation of
toxicant or prevent its formation are called reactive oxygen and nitrogen species (ROS and RNS).
detoxications.
• Cell injury progresses toward cell necrosis (death) if
• Apoptosis, or programmed cell death, is a tightly molecular repair mechanisms are inefficient, or the
controlled, organized process whereby individual molecular damage is not readily reversible.
cells break into small fragments that are
• Chemical carcinogenesis involves insufficient function
phagocytosed by adjacent cells or macrophages
of various repair mechanisms, including (1) failure of
without producing an inflammatory response. DNA repair, (2) failure of apoptosis (programmed cell
death), and (3) failure to terminate cell proliferation.

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Introduction

• Commonly, a toxicant is delivered to its target, reacts with it, and

the resultant cellular dysfunction manifests itself in toxicity.

• Sometimes a xenobiotic does not react with a specific target

molecule but rather adversely influences the biological
environment, causing molecular, organellar, cellular, or organ
dysfunction leading to deleterious effects.

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Step 1 - Delivery
From the site of exposure to the target

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Delivery

• Commonly, a toxicant is delivered to its target,

reacts with it, and the resultant cellular dysfunction
manifests itself in toxicity.

• Sometimes a xenobiotic does not react with a

specific target molecule but rather adversely
influences the biological environment, causing
molecular, organellar, cellular, or organ
dysfunction leading to deleterious effects.

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Absorption versus Presystemic Elimination

ABSORPTION P R E S Y S T E M I C E L I M I N AT I O N

• The transfer of a chemical from the site of • During transfer from the site of exposure
exposure, usually an external or internal to the systemic circulation, toxicants may
body surface, into the systemic circulation be eliminated.

• Also known as first-pass elimination.

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Distribution to and away from the Target
M E C H A N I S M S FA C I L I TAT I N G D I S T R I B U T I O N T O A TA R G E T M E C H A N I S M S O P P O S I N G D I S T R I B U T I O N T O A TA R G E T

• Porosity of the Capillary Endothelium • Binding to Plasma Proteins

• Specialized Transport Across the Plasma • Specialized Barriers

Membrane
• Distribution to Storage Sites
• Accumulation in Cell Organelles
• Association with Intracellular Binding
• Reversible Intracellular Binding Proteins

• Export from Cells

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Excretion versus Reabsorption
EXCRETION
• Excretion is the removal of xenobiotics
from blood and their return to the external
environment.
• Excretion is a physical mechanism,
whereas biotransformation is a chemical
mechanism for eliminating the toxicant.
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REABSORPTION
• Toxicants delivered into the renal tubules may diffuse
back across the tubular cells into the peritubular
capillaries. This tubular fluid reabsorption increases the
intratubular concentration as well as the residence time
of the chemical by slowing urine flow.
• Reabsorption by diffusion is dependent on the lipid
solubility of the chemical and inversely related to the
extent of ionization, because the nonionized molecule is
more lipid soluble.
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Toxication versus Detoxication
T O X I C AT I O N
• Biotransformation to harmful products is
called toxication or metabolic activation.
• With some xenobiotics, toxication confers
physicochemical properties that adversely
alter the microenvironment of biological
processes or structures.
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D E T O X I C AT I O N
Biotransformations that eliminate the ultimate toxicant or
prevent its formation are called detoxications. In some
cases, detoxication may compete with toxication.
• Detoxication of Toxicants with No Functional Groups
• Detoxication of Nucleophiles
• Detoxication of Electrophiles
• Detoxication of Free Radicals
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Detoxication of Free Radicals
• Because O2*- can be converted into
much more reactive compounds, its
elimination is an important
detoxication mechanism (e.g. NO3)

• It is reactive toward DNA and

proteins.

• ONOO reacts nucleophilically with

carbon dioxide.

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Detoxication of Free Radicals
• Superoxide dismutases (SODs),
located in the cytosol (Cu, Zn-SOD)
and the mitochondria (Mn-SOD),
convert O2*- to H2O2.

• Subsequently, H2O2 is reduced to

water by cytosolic glutathione
peroxidase or peroxisomal catalase

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Step 2 - Reaction
Reaction of the Ultimate Toxicant with the
Target Molecule

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Reaction

• Toxicity is typically mediated by a reaction of the ultimate

toxicant with a target molecule (step 2a).

• Subsequently, a series of secondary biochemical events occur,

leading to dysfunction or injury that is manifest at various levels
of biological organization, such as at the target molecule itself,
cell organelles, cells, tissues and organs, and even the whole
organism.

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Attributes of Target Molecules
• Practically all endogenous compounds are potential targets for toxicants.

• The most prevalent and toxicologically relevant targets are nucleic acids (especially DNA), proteins, and
membranes. The first target for reactive metabolites is often the enzyme responsible for their production
or the adjacent intracellular structures.

• Not all targets for chemicals contribute harmful effects.

• To conclusively identify a target molecule as being responsible for toxicity, it should be demonstrated that
the ultimate toxicant
1. Reacts with the target and adversely affects its function,

2. reaches an effective concentration at the target site, and

3. alters the target in a way that is mechanistically related to the observed toxicity.

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