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Questions and Answers
What is toxicology?
What is toxicology?
Toxicology is the study of the adverse effects of xenobiotics on living organisms.
Who famously said, 'All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy'?
Who famously said, 'All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy'?
Toxicity refers to any effect that a chemical may have on living organisms.
Toxicity refers to any effect that a chemical may have on living organisms.
True
_____ is defined as the expected frequency of the occurrence of an undesirable effect from exposure to a chemical or physical agent.
_____ is defined as the expected frequency of the occurrence of an undesirable effect from exposure to a chemical or physical agent.
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Match the term with its definition:
Match the term with its definition:
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What is biotransformation?
What is biotransformation?
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Which family of enzymes mediate glucuronidation, sulfation, and methylation in Phase 2 of metabolism?
Which family of enzymes mediate glucuronidation, sulfation, and methylation in Phase 2 of metabolism?
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CYP450 enzymes function as monooxygenases.
CYP450 enzymes function as monooxygenases.
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The _____ family of enzymes mediate the luminal transport of molecules in tubular secretion.
The _____ family of enzymes mediate the luminal transport of molecules in tubular secretion.
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Match the conjugation with its process:
Match the conjugation with its process:
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How does passive diffusion work for absorption of molecules?
How does passive diffusion work for absorption of molecules?
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What type of molecules is rapid for passive diffusion?
What type of molecules is rapid for passive diffusion?
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Facilitated diffusion requires carrier molecules to transport molecules through the cell membrane.
Facilitated diffusion requires carrier molecules to transport molecules through the cell membrane.
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Active transport requires __________ (molecule) to pump molecules against a concentration gradient.
Active transport requires __________ (molecule) to pump molecules against a concentration gradient.
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Match the following mechanisms with their functions:
Match the following mechanisms with their functions:
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What does bioavailability represent?
What does bioavailability represent?
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What is the cofactor for methylation in the context of xenobiotic biotransformation?
What is the cofactor for methylation in the context of xenobiotic biotransformation?
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Which enzyme is responsible for the methylation of the neurotransmitter norepinephrine?
Which enzyme is responsible for the methylation of the neurotransmitter norepinephrine?
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Detoxification reactions eliminate toxicants from the body.
Detoxification reactions eliminate toxicants from the body.
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_______ can react with electrophiles to facilitate detoxification.
_______ can react with electrophiles to facilitate detoxification.
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Which type of binding is practically irreversible?
Which type of binding is practically irreversible?
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What type of receptor does Warfarin act on?
What type of receptor does Warfarin act on?
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Botulinum toxin acts as a Zn-protease.
Botulinum toxin acts as a Zn-protease.
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Snake venoms contain hydrolytic enzymes that destroy ____________.
Snake venoms contain hydrolytic enzymes that destroy ____________.
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Match the following toxins with their enzymatic actions:
Match the following toxins with their enzymatic actions:
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Study Notes
Here are the study notes:
Overview of Toxicology
- Toxicology is the study of the adverse effects of xenobiotics on living organisms
- Deals with foods, cosmetics, and other substances for public consumption, both in living and dead victims
- Includes the study of the qualitative and quantitative effects of chemicals on organisms
History of Toxicology
- Developed from "Material Medica"
- Historically, toxicology formed the basis of therapeutics and experimental medicine
- In ancient times, toxicology was used for hunting, warfare, and assassination
- Key contributors to the field of toxicology include Dioscorides, Maimmonides, Paracelsus, and Orfila
Toxicology Today
- Now a multidisciplinary science that includes environmental toxicology, molecular toxicology, and clinical toxicology
- Environmental toxicologists study the effects of chemicals on flora and fauna
- Molecular toxicologists study the mechanisms of toxicants on cell growth and differentiation
- Clinical toxicologists develop antidotes and treatment regimens for poisonings
Toxicological Terms and Definitions
- Toxin: a poison of natural origin
- Poison: a chemical that may harm or kill an organism
- Toxic: having the characteristic of producing an undesirable or adverse health effect
- Toxity: the adverse effect of a chemical on an organism
- Hazard: the likelihood of injury from a chemical or physical agent
- Risk: the expected frequency of an undesirable effect from exposure to a chemical or physical agent
Toxic Doses and Response
- Median Lethal Dose (LD50): the dose expected to kill 50% of a population
- Median Effective Dose (ED50): the dose producing a desired response in 50% of a population
- Median Toxic Dose (TD50): the dose producing a toxic effect in 50% of a population
- Therapeutic Index (TI): the ratio of LD50 to ED50
- Highest Nontoxic Dose (HNTD): the largest dose that does not produce hematological, chemical, clinical, or pathological alterations
- Toxic Dose Low (TDL): the lowest dose producing drug-induced alterations
- Toxic Dose High (TDH): the dose producing drug-induced alterations, with twice the dose causing death
Chemical Interactions
- Potentiation: the enhanced toxic effect of one chemical in the presence of another
- Additive: the combined effect of two chemicals equal to the sum of individual effects
- Synergistic: the combined effect of two chemicals greater than the sum of individual effects
- Antagonistic: preventing agonist chemicals from reaching cell receptor sites
Routes of Exposure and Absorption
- Toxicokinetics: the study of the absorption, distribution, and elimination of toxic substances
- Routes of exposure: inhalation, ingestion, dermal absorption, and injection
- Absorption: the process by which a toxicant enters the body
- Distribution: the movement of a toxicant throughout the body
- Elimination: the process by which a toxicant is removed from the body### Mechanisms Facilitating Distribution to a Target
- pH trapping: diffusion of amphipathic xenobiotics with a protonable amine group into acidic organelles (e.g., lysosomes), where they become protonated, preventing efflux, and inhibit lysosomal phospholipases, leading to phospholipidosis.
- Reversible intracellular binding: binding to non-target sites, reducing the concentration of toxicants at the target site, and temporarily minimizing effects.
- Distribution to storage sites: accumulation of chemicals in tissues (e.g., adipose tissue, bone) where they do not exert significant effects, acting as a temporary protective mechanism.
Association with Intracellular Binding Proteins
- Export from cells: ATP-dependent membrane transporters (e.g., P-glycoprotein) facilitate the removal of intracellular toxicants from cells.
Distribution
- Protein binding: proteins are too large to leave capillaries, so drug-protein complexes become trapped, and only free or unbound drugs can leave the capillaries.
Elimination
- Biotransformation: enzyme-mediated transformation of compounds, converting lipophilic to hydrophilic, facilitating excretion.
- Consequences of biotransformation: reduced half-life, duration of exposure, and accumulation, while changing the biological activity of the xenobiotic.
Excretion versus Reabsorption
- Glomerular filtration: higher blood pressure in the glomerulus increases the number of particles filtered.
- Tubular secretion: active transport of certain molecules, facilitated by transporters specialized for hydrophilic organic acids and bases.
- Tubular reabsorption: depends on lipid solubility and molecule size, with some efficient mechanisms for removing hydrophilic compounds, but not lipophilic chemicals.
Metabolism and Toxicology
- CYP450: a major enzyme involved in xenobiotic biotransformation, with various isoforms (e.g., CYP3A4, CYP2D6) that metabolize different substrates.
Conjugation
- Glucuronidation, sulfonation, acetylation, and methylation: reactions that increase xenobiotic hydrophilicity, promoting excretion.
- Glucuronidation: a major detoxification pathway, involving reactions with activated or "high-energy" cofactors.
Drug Metabolism/Biotransformation
- Excretion: may occur through the urine or bile, with some conjugates undergoing enterohepatic cycling, leading to delayed drug elimination.
Glutathione Conjugation
- Glutathione transferases: catalyze the transfer of glutathione to reactive electrophiles, protecting the cellular environment from damage.
- Substrates: share features such as hydrophobicity, electrophilic atoms, and reactivity with glutathione.
Sulfonation
- Sulfotransferases: two classes, membrane-bound and soluble, involved in the sulfonation of endogenous peptides and xenobiotics, respectively.
Methylation
- A common but minor pathway of xenobiotic biotransformation, decreasing water solubility and masking functional groups.
Amino Acid Conjugation
- Two pathways: conjugation of xenobiotics with glycine, glutamine, and taurine, and conjugation of aromatic hydroxylamines with serine and proline.
Toxication versus Detoxification
- Toxification: biotransformation to harmful products, involving the formation of electrophiles, which can react with endogenous molecules.
- Detoxification: biotransformation to harmless products, facilitating excretion.### Toxification Mechanisms
- Free radicals: molecules or molecular fragments with one or more unpaired electrons in their outer orbital
- Nucleophiles: rare among biomolecules, can be reactive (e.g., HCN, CO, H2S, N=N) and form coordinate covalent bonds with iron in hemeproteins
- Redox-active reactants: can activate nucleophiles by converting them to electrophiles
Detoxification
- Biotransformation that eliminates an ultimate toxicant or prevents its formation
- Competes with toxification for a chemical
- Two-phase process:
- Introduction of a functional group (e.g., hydroxyl or carboxyl) by cytochrome-P450 enzymes
- Addition of an endogenous acid (e.g., glucuronic acid, sulfuric acid, or an amino acid) to the functional group by a transferase
Detoxification of Different Compounds
- Nucleophiles: hydroxylated compounds are conjugated by sulfation, glucuronidation, or methylation
- Electrophiles: conjugation with thiol nucleophile glutathione, facilitated by glutathione S-transferases
- Free radicals: detoxified by superoxide dismutases (SOD) and catalase in peroxisomes
- ONOO- (peroxynitrite): more stable than HO, reacts with CO2, and can be detoxified by glutathione peroxidase
When Detoxification Fails
- Toxicants can overwhelm detoxification processes, leading to enzyme saturation, cosubstrate consumption, and antioxidant depletion
- Reactive toxicants can inactivate detoxification enzymes
- Conjugation reactions can be reversed, and detoxification may generate harmful by-products
Mechanism of Toxicity
- Tetrodotoxin (puffer fish poison) blocks voltage-gated Na+ channels of motoneurons, leading to skeletal muscle paralysis
- 2,4-dinitrophenol: collapses the proton gradient across the inner mitochondrial membrane, causing mitochondrial dysfunction and hyperthermia
Reaction of the Ultimate Toxicant with the Target Molecule
- To identify a target molecule as responsible for toxicity, it must:
- Reach an effective concentration at the target site
- React with the target and adversely affect its function
- Alter the target in a way that is mechanistically related to the observed toxicity
- Targets are often endogenous molecules exposed to reactive chemicals or adjacent to the site of action
- Reactive metabolites can diffuse and react with adjacent structures or targets
Bonding
- Non-covalent binding: reversible, due to polar interactions, hydrogen bonds, and ionic bonds
- Covalent binding: practically irreversible, permanently alters endogenous molecules, and is toxicologically important
Effects of Toxicants on Target Molecules
- Dysfunction of target molecules: inhibition, blockage, or alteration of function
- Activation of protein targets or mimicking endogenous ligands
- Destruction of target molecules: neoantigen formation, immune response, and altered protein function
- Toxicity not initiated by reaction with target molecules: alteration of biological microenvironment
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Description
This quiz covers the basics of toxicology, including its history, definitions, and differences from pharmacology. It also discusses the importance of toxicology and its interdisciplinary nature.
