WK 3 Mechanisms of Toxicity: Cellular Targets and Metabolic Bioactivation

Vocabulary flashcards detailing cellular and biochemical mechanisms of toxicity, oxidative stress, mitochondrial disruption, and metabolic bioactivation pathways including alcohol and acetaminophen toxicity.

Biological Target

A specific biomolecule or cellular component—such as an enzyme, receptor, membrane lipid, transporter, or DNA—with which a toxic chemical or its metabolite interacts.

Cellular Response

The downstream alterations in cell signaling, metabolism, or physical structure triggered by a toxicant's interaction with a biological target.

Cellular Consequence

The ultimate biological outcome of toxic exposure, in which cells successfully adapt, recover after stressor removal, or suffer sustained injury and death.

Oxidative Stress

A cellular state that occurs when the production of reactive oxidants exceeds the cell's enzymatic and non-enzymatic antioxidant protective capacity.

Reactive Oxygen Species (ROS)

Chemically reactive oxygen-containing molecules generated naturally for signaling and metabolism that can damage macromolecules if overproduced.

Membrane Lipid Oxidation

Oxidative degradation of cell membrane lipids by reactive oxidants, resulting in impaired membrane permeability, disrupted ion gradients, and altered signaling.

Direct Mitochondrial Disruption

Toxicity caused by toxicant interactions that alter the electron transport chain or mitochondrial membrane potential, directly reducing oxidative ATP synthesis.

Oxidant-Related Mitochondrial Injury

Mitochondrial dysfunction caused by an oxidant imbalance that damages structural and functional mitochondrial components.

Enzyme Inhibition

The process by which an inhibitor blocks an enzyme's active site or function, resulting in decreased product formation and accumulation of the substrate.

Organophosphate Toxicity Mechanism

The inhibition of the enzyme acetylcholinesterase (AChE) at synapses, which prevents acetylcholine breakdown and causes continuous signal transmission.

Receptor Agonist

A signaling molecule or exogenous chemical that binds to a receptor and activates it, triggering downstream changes in gene transcription or cell behavior.

Receptor Antagonist

A compound that binds to a specific biological receptor and blocks its activation by endogenous signaling molecules.

DNA Damage

Physical or chemical lesions—including adducts, strand breaks, and replication errors—that threaten genomic integrity and activate DNA repair mechanisms.

Gene Regulation

The control of which genes are expressed through transcriptional changes or epigenetic alterations without altering or damaging the DNA sequence itself.

DDT

Dichlorodiphenyltrichloroethane; a persistent synthetic pesticide developed to control agricultural pests and mosquitoes that bioaccumulates and biomagnifies in ecosystems.

DDE

A persistent breakdown metabolite of DDT that interferes with calcium metabolism in birds, leading to eggshell thinning and reproductive failure.

Eggshell Thinning

A reproductive pathology caused by DDE that led to severe population declines in predatory bird species such as bald eagles, ospreys, and peregrine falcons.

Biomagnification

The progressive bioaccumulation and increase in toxicant concentration at successively higher trophic levels within a food web.

Silent Spring

The 1962 landmark book written by Rachel Carson that documented the ecological hazards of persistent chemical pesticides like DDT and launched the modern environmental movement.

Alcohol Dehydrogenase (ADH)

A hepatic enzyme responsible for the first step of alcohol metabolism, oxidizing ethanol into the reactive intermediate acetaldehyde.

Acetaldehyde

A reactive intermediate metabolite formed during alcohol breakdown that can bind cellular proteins and trigger flushing, nausea, and rapid heartbeat.

Aldehyde Dehydrogenase (ALDH)

A liver enzyme that metabolizes reactive acetaldehyde into acetate, a significantly less reactive compound.

ALDH2*2 Variant

A genetic mutant allele of mitochondrial aldehyde dehydrogenase 2 that exhibits reduced clearance activity, causing acetaldehyde buildup upon alcohol ingestion.

Alcohol Flushing Response

An adverse reaction characterized by facial reddening, nausea, and elevated heart rate resulting from impaired acetaldehyde breakdown due to an ALDH2 enzyme deficiency.

Acetaminophen (APAP)

A common analgesic and antipyretic drug that undergoes bioactivation into a hepatotoxic intermediate when therapeutic dosages are exceeded.

Cytochrome P450 (CYP450)

The hepatic hemeprotein enzyme system responsible for metabolizing a fraction ($15\%$) of absorbed acetaminophen into reactive NAPQI.

NAPQI

N-acetyl-p-benzoquinone imine; a reactive, electrophilic metabolite of acetaminophen that causes hepatocellular necrosis when protective stores are exhausted.

Glutathione (GSH)

An endogenous protective tripeptide in hepatocytes that conjugates and neutralizes NAPQI; its depletion allows NAPQI to react covalently with cell proteins.

N-acetylcysteine (NAC)

A therapeutic antidote clinically administered for acetaminophen overdose that acts by replenishing glutathione availability to neutralize NAPQI.

ADME

Absorption, Distribution, Metabolism, and Excretion; the pharmacokinetic processes that determine the systemic fate and target-site concentration of a toxicant.