Cytotoxicity, Tissue

Injury, and Target OHS 322

Organs INTRODUCTORY TOXICOLOGY

Dr. Rob Moriarity
 Outline
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1. Cytotoxicity
1.1 Direct
1.2 Indirect

2. Types of Tissue Injury

3. Target Organs
3.1 Assessment and Biomarkers of Organ Toxicity

4. Current Literature

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 Toxicity
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Toxicant

Delivery

Alt. of Biol. Env. Interaction with Target Organ

Cellular Dysfunction and Injury

Disrepair Toxicity

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 Factors Influencing Toxicity
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• Route of exposure
• Dose
• Duration and frequency of exposure
• Interactions
• Individual susceptibility

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 Introduction to Cytotoxicity
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• Cytotoxicity: The quality of being toxic to cells.

• Involves mechanisms
• Critical for evaluating the safety and therapeutic efficacy of pharmaceuticals.

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 Overview of Cell Injury
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• Cells control their environment and intracellular milieu within physiological

parameters for homeostasis.

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 Agents of Cell Injury
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• Oxygen
• Physical agents
• Chemical agents
• Infectious agents
• Immunologic reactions
• Genetic defects
• Dietary factors

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Mechanisms of Cellular Injury
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Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed.

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 Disruption of Cellular Membranes
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• Cell membranes maintain the cell’s internal environment, controlling the

exchange of substances.

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Results of Membrane Damage
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 Inhibition of Protein Synthesis
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• Protein synthesis is crucial for cell maintenance and response to environmental

stimuli.

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 Indirect Cellular Damage
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• Generation of reactive oxygen species (ROS) induces oxidative stress, damaging

cellular components.
• Induction of inflammation can lead to further cellular damage through the
immune response.

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 Reactive Oxygen Species (ROS)
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• Definition and types of ROS: superoxide, hydrogen peroxide, hydroxyl radical.

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 Free Radicals: Formation and Action
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• Chemical characteristics of free radicals.

• Mechanisms of free radical formation: endogenous and exogenous sources.
• Roles in normal cellular functions and pathological conditions.

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Origin of Free Radicals
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 Enzymes
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• Phase I specifically

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 Intracellular Sources
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• Normal redox reactions generate free radicals

• Nitric oxide (NO) can act as a free radical
• Ionizing radiation (UV, X-rays) can hydrolyze water into hydroxyl (OH· ) and
hydrogen (H· ) free radicals
• Metabolism as CCl4 can generate free radicals

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 Oxidative Stress & ROS
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• Life developed in the presence of approximately 20% oxygen

• Oxygen forms free radicals: superoxide (O− 2 ), hydrogen peroxide (H2 O2 ), hydroxyl
1
radical (OH ), singlet oxygen ( O2 ), nitric oxide (NO· ), peroxynitrite (ONOO− )
·

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Free Radical-Induced Injury
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 Cellular Responses to ROS Damage
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• Antioxidant defense mechanisms: enzymatic and non-enzymatic antioxidants.

• Signal transduction pathways activated by ROS.
• Cell death pathways: apoptosis, necrosis, and autophagy.

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 Role of ROS in Disease
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• Contribution of ROS to cancer, cardiovascular diseases, and neurodegeneration.

• The dual role of ROS in cell signaling and disease progression.

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 Antioxidant Defense Mechanisms
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• Overview of cellular antioxidants: Glutathione, superoxide dismutase, catalase.

• Dietary antioxidants and their role in health.

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 Reducing Oxidative Stress
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• Lifestyle and dietary modifications.

• Pharmacological interventions: antioxidants and free radical scavengers.
• Advances in targeted therapies for oxidative stress-related diseases.

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Necrosis vs. Apoptosis
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 Necrosis
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• ROS impact varies by dose:

— Low Dose: Growth arrest, Senescence
— Intermediate: Mitogenic, Proliferative, Regulation of gene expression
— High Dose: Cell Death

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 Etiology of Tissue Necrosis
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• Hypoxia
• Physical injury
• Chemicals
• Biological toxins
• Immunological reactions
• Genetic disorders
• Nutritional factors

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Mechanisms of Necrosis
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Signs of Necrosis
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Types of Necrosis
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 Autophagy and Cell Survival/Death
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• Autophagy: A cellular process for degrading and recycling cellular components.

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 Injury
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• Acute Injury:
— Rapid onset
— Symptoms are severe but can be short-lived

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Injury
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• Chronic Injury:
— Results from prolonged
exposure
— Symptoms develop
gradually and can persist

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Tissue Damage
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 Tissue Repair (Healing)
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• Regeneration of injured tissue (replacement by normal cells of the same kind)

• Replacement by fibrous tissue (fibrosis, scarring)

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 Regeneration
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• The ability of a tissue to replace damaged cells with new cells of the same type.
• Key to restoring the original structure and function of the tissue.

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 Fibrosis
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• The replacement of damaged tissue with scar tissue, composed mainly of collagen.

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 Type of Toxicant and Exposure
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• The chemical nature of the toxicant can determine the type and severity of tissue
injury.
• Both the dose and duration of exposure are critical.

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 Susceptibility and Genetic Factors
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• Genetic makeup can influence an individual’s ability to metabolize or detoxify

harmful substances.

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 Concept of Target Organs
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• Specific organs or tissues most affected by exposure to a particular toxicant.

• Factors determining organ specificity include the route of exposure, ADME.

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 To the Target Organ
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• Toxicant enters the blood

• Circulates in the body
• Enters cells
• Distribution to the targets may be enhanced by:
— Porosity
— Transport
— Receptors
— Binding

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 Opposing Distribution to a Target
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• Binding to plasma proteins

• Specialized barriers
• Distribution to storage site
• Association to intracellular binding proteins
• Export from cells

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 Metabolic Activation - Liver Injury
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• Liver metabolizes toxic substances; lipophilic compounds to hydrophilic.

• Examples include the metabolism of acetaminophen into NAPQI

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 Oxidative Stress in Hepatotoxicity
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• Reactive oxygen species (ROS) produced during metabolism

• Excessive ROS → oxidative stress, damaging lipids, proteins, DNA
• Overwhelmed antioxidant defense → cell injury, death

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 Immune-mediated Liver Damage
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• Liver: immune surveillance, site of immune-mediated damage

• Hepatotoxicants alter liver cell antigens, induce neoantigens
• Immune attack → inflammation, hepatocyte destruction (e.g., DILI)

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 Direct Toxin Effects on Renal Cells
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• Kidneys highly vascularized, exposed to circulating toxicants

• Direct toxicity → acute tubular necrosis, AKI
• Common causes: antibiotics (aminoglycosides), heavy metals (mercury)

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 Nephrotoxicity
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• Glomeruli filter blood, damage impairs kidney function

• Toxicants cause glomerulonephritis, proteinuria, reduced filtration
• Immune responses to infections, diseases can also damage glomeruli

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 Obstruction of Urinary Pathways
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• Drugs, toxins precipitate in kidneys, form crystals

• Obstruction leads to hydronephrosis, renal failure
• Examples: uric acid crystals in malignancy treatment, sulfonamides

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 Inhalation of Toxins and Particles
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• Lung’s direct interface with environment → susceptible to inhaled toxicants

• Acute exposure to irritant gases (e.g., chlorine, ammonia) → pulmonary edema,
ARDS
• Chronic exposure to particulate matter (e.g., silica, asbestos) → COPD, fibrosis

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 Respiratory Toxicity
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• Inhalation of toxicants → inflammatory response, chronic inflammation, tissue

damage
• Persistent inflammation → exacerbate pre-existing conditions (e.g., asthma),
bronchitis, pulmonary fibrosis
• Long-term exposure to air pollutants (e.g., fine particulate matter, ozone) →
significant risk factor

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 Fibrosis/Chronic Respiratory Conditions
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• Fibrosis → excess fibrous connective tissue formation

• Scarring reduces lung capacity, elasticity → difficulty breathing, reduced oxygen
exchange
• Asbestos exposure → mesothelioma, fibrotic lung disease

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 Direct Neuronal Damage
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• Neurons highly sensitive to toxic insults → direct damage to structure, function

• Toxicants (e.g., lead, mercury) damage neuronal cells → cognitive deficits, motor
disturbances
• Pesticides inhibit critical enzymes → neurodegenerative effects

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 Alteration of Neurotransmitters
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• Neurotoxicants disrupt neurotransmitter balance

• Organophosphates inhibit acetylcholinesterase → acetylcholine accumulation,
overstimulation
• Disruption → mood disorders, memory loss, impaired motor function

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 Disruption of Neuronal Networks
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• Toxic substances disrupt neuronal networks

• Solvents (e.g., toluene) affect myelin sheath → demyelinating diseases, signal
transmission
• Key feature in neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s)

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 Biomarkers of Organ Toxicity
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• Tools for assessing organ function: imaging techniques, functional tests,

histopathological examination
• Biomarkers: specific molecules indicating extent of exposure or injury to an organ
(e.g., enzymes, proteins, DNA adducts)
• Significance of biomarkers: detect early signs of toxicity, monitor disease
progression, guide therapeutic interventions

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 Cytotoxic Plant Derivatives
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• Essential oil from Vitex gardneriana showed cytotoxic effects at specific

concentrations.

molecules
Review
The Cytotoxic and Inhibitory Effects of Plant Derivatives on
Candida albicans Biofilms: A Scoping Review
Manuela Loaiza-Oliva , Laura Arias-Durango and María Cecilia Martínez-Pabón *

Laboratory of Oral Microbiology, Faculty of Dentistry, Universidad de Antioquia, Medellín 050010, Colombia
* Correspondence: [email protected]

Abstract: Candida albicans infections are related to biofilm formation. The increase in antifungal
resistance and their adverse effects have led to the search for therapeutic options as plant derivatives.
This scoping review aims to identify the current status of in vitro research on the cytotoxicity and in- 55 / 59
hibitory effects of plant derivatives on C. albicans biofilms. In this study, PRISMA items were followed.
 Cytotoxic Effects of Mycotoxins
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• Co-treatment with two known toxicants exhibited synergism.

International Journal of
Molecular Sciences

Article
In Vitro Evaluation of the Individual and Combined Cytotoxic
and Estrogenic Effects of Zearalenone, Its Reduced Metabolites,
Alternariol, and Genistein
Adrienn Balázs 1,† , Zelma Faisal 2,3,† , Rita Csepregi 4,5 , Tamás Kőszegi 3,4,5 , Balázs Kriszt 6 , István Szabó 1
and Miklós Poór 2,3, *

1 Department of Environmental Toxicology, Institute of Aquaculture and Environmental Safety,

Hungarian University of Agriculture and Life Sciences, Páter Károly u. 1, H-2100 Gödöllő, Hungary;
[email protected] (A.B.); [email protected] (I.S.)
2 Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary;
[email protected]
3 Food Biotechnology Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20,
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H-7624 Pécs, Hungary; [email protected]
4
 Cytotoxicity of Tamarix nilotica
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• Chemical composition and cytotoxic potential of Tamarix nilotica flowers explored.

Fayed et al. BMC Complementary
BMC Complementary Medicine and Therapies (2023) 23:169
https://doi.org/10.1186/s12906-023-03989-8 Medicine and Therapies

RESEARCH Open Access

Chemical profiling and cytotoxic

potential of the n-butanol fraction of Tamarix
nilotica flowers
Marwa A. A. Fayed1*† , Riham O. Bakr2, Nermeen Yosri3†, Shaden A. M. Khalifa4, Hesham R. El-Seedi5,6,7,8,
Dalia I. Hamdan9 and Mohamed S. Refaey1

Abstract
Background Cancer represents one of the biggest healthcare issues confronting humans and one of the big chal-
lenges for scientists in trials to dig into our nature for new remedies or to develop old ones with fewer side effects. 57 / 59
 Diterpenoid Alkaloids vs. Cancer
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• Tested lycoctonine-type alkaloids for cytotoxicity against human cancer cells.

molecules
Review
Cytotoxic E↵ects of Diterpenoid Alkaloids Against
Human Cancer Cells
Koji Wada * and Hiroshi Yamashita
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 4-1,
Maeda 7-jo 15-choume, Teine-ku, Sapporo 006-8590, Japan; [email protected]
* Correspondence: [email protected]; Tel.: +81-11-681-2161

Academic Editor: Kyoko Nakagawa-Goto !"#!$%&'(!

!"#$%&'
Received: 23 May 2019; Accepted: 21 June 2019; Published: 22 June 2019

Abstract: Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya
(Ranunculaceae) and classified according to their chemical structures as C18 -, C19 - or C20 -diterpenoid 58 / 59
 Reminders
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• Homework assignment due March 6, 2025

• Quiz #2, March 7, 2025 (9:00 AM to 5:00 PM)
• March 14: Teratology, Genetic Toxicity and Developmental Toxicity will be
recorded

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