Clinical Toxicology Overview

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:
  1. Introduction of a functional group (e.g., hydroxyl or carboxyl) by cytochrome-P450 enzymes
  2. 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:
  1. Reach an effective concentration at the target site
  2. React with the target and adversely affect its function
  3. 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