Chemistry of Toxicology - Lecture 2

Chemistry of Toxicology - Lecture 2

• Toxicology studies the adverse effects of chemicals on living organisms
• Xenobiotics are substances foreign to an organism
• Xenobiotics are broken down through a process called metabolism
• Metabolism describes the biochemical changes that substances undergo in the body
• Metabolism changes a substance into various metabolites and some may be more toxic than the original compound
• Metabolites are excreted by various pathways
• Metabolism is critical for toxic action
• Some chemicals can cause toxic effects when metabolized
• Excretion removes these harmful compounds/metabolites from the body
• Excretion occurs through various parts of the body

• Kidney 
  

• Liver
  

• Lungs
  

• Sweat
  

• Saliva
  

• Tears
  

Pathways of Xenobiotic Species

• Xenobiotics are first metabolized before they can cause toxicity
• Substances are either detoxified or metabolized to a more toxic form
• Unchanged compounds can also be excreted
• Active metabolites can undergo further biochemical interaction

Metabolism

• The biochemical changes substances undergo in a living organism are called metabolism
• Metabolism breaks down chemical species
• Metabolism builds up new molecules, requiring energy for this process
• Metabolism provides two essential components: energy and raw materials
• Metabolism is important for toxicological chemistry
• Toxic effects can arise from interference with metabolism
• Toxicants can be transformed into less toxic forms, allowing for easier elimination from the body

Metabolism - Pathways

• Nutrients and xenobiotics enter the gastrointestinal tract
• Substances are broken down and transported into the bloodstream
• Most substances are transported through the intestinal walls to liver
• Liver metabolizes chemicals and plays a critical role
• Oxygen enters the bloodstream through the lungs

Biotransformation

• Biotransformation alters xenobiotic compounds, primarily through enzyme action
• Enzymatic and non-enzymatic reactions are involved
• Non-enzymatic reactions can cause bond formation with endogenous compounds, hydrolysis, or oxidation/reduction processes.
• The likelihood for biotransformation depends on the chemical nature of the xenobiotic
• Compounds with high polarity may be less absorbed and quickly excreted
• Those compounds resistant to enzymatic attack accumulate in lipid tissue

Biotransformation - Processes affecting

• Volatile compounds (e.g., dichloromethane, diethyl ether) are rapidly excreted by the respiratory system, so enzymatic metabolism is relatively less important for them
• Lipophilic compounds are more likely to accumulate in lipid tissues
• Xenobiotic metabolism can occur in various tissues throughout the body
• Key sites for metabolism include skin and lungs
• Liver is vital; materials entering the bloodstream from the digestive system pass through the liver first

Major Sites of Exposure, Metabolism and Storage and Elimination

• Major pathways for entry include ingestion, inhalation, and dermal exposure
• Chemicals in the gastrointestinal tract are processed before entering the bloodstream
• Processed compounds are transported to the liver for further metabolism
• Oxygen enters the bloodstream through the lungs
• Some substances are excreted by the kidneys
• Substances in the urine leave the body through the bladder
• Liver expels substances into bile, and they are excreted through the feces
• Exhalation removes carbon dioxide

Metabolism - Important Pathways for Excretion

• Volatile substances often enter the blood through the lungs
• Undigested food residues and liver waste leave the body in feces
• Urine produced by the kidneys and bladder eliminates metabolic waste products
• Waste carbon dioxide is eliminated through the lungs

Metabolism

• The process where a chemical (parent compound) is changed
• The chemical becomes more water soluble allowing easier excretion from the body
• Decreasing lipid solubility decreases amount of substance at target sites
• Increasing ionization rate increases excretion rate

Bioactivation

• Certain chemicals become more toxic through metabolic processes
• Substances can be transformed into compounds that are equally or more toxic than the original compound

Reactions of Metabolism

• Two primary phases (I and II) are involved in metabolic processes
• Phase I reactions introduce reactive, polar functional groups into initially lipophilic, nonpolar compounds (making them more polar/water soluble)
• Phase II reactions couple the compounds to soluble endogenous molecules making them more readily excreted

Phase I and Phase II Reactions (continued)

• Phase I reactions change the chemical structure of a xenobiotic by oxidizing, reducing or hydrolyzing it, making it more water-soluble
• The substance usually forms a more water-soluble compound
• Phase II reactions chemically conjugate the compound with water soluble molecules (more easily excreted)
• This makes the original substance more easily excreted from the body

Oxidation, Reduction, Hydrolysis

• Oxidation, reduction, and hydrolysis are frequently used in phase I reactions
• Oxidation of carbon, nitrogen, sulfur and phosphorus are commonly seen

Excretion

• Kidneys are the main excretory organ for various toxins, and carry out glomerular filtration and tubular secretion.
• The liver can also excrete substances via biliary excretion.
• Lungs excrete volatile compounds

Urinary pH Trapping

• Urinary pH affects excretion of drugs
• Changing the urine's acidity or alkalinity can alter the absorption of some drugs

Tubular Secretion

• Kidney's proximal renal tubules use transporters to actively secrete anionic and cationic drugs
• Certain drugs (e.g. penicillin) may be actively secreted into the filtrate
• Other compounds may compete for the same transporters, influencing the rates of excretion

Biliary Excretion

• Toxicants can be secreted into bile by the liver
• Bile carries substances to the small intestine where they are excreted in the stool
• Liver damage can reduce biliary excretion leading to an accumulation of toxic substances

Toxicodynamics

• Effects of a chemical on the body, depending on its concentration at the target site

• Certain organs are more susceptible than others, based on blood flow and metabolic reactions

• Target organs include liver, kidneys, lungs, and neurons.

• Adverse reactions are dependent on the concentration of a chemical at target sites and duration of exposure.

• Modification of Carriers: toxins/chemicals can change the structure or function of carriers within cells; e.g., hemoglobin and carbon monoxide.

• Interference with Coenzymes: toxins/chemicals can inhibit/destroy coenzymes, critical for a number of metabolic reactions

• Formation of Reactive Metabolites: some substances become toxic when converted to reactive metabolites.

• Reactions depleting GSH: loss of this antioxidant can lead to greater cellular damage.

• Action on Nucleic Acids: toxins/chemicals can damage DNA and RNA, interfering with protein synthesis.

• Alteration of protein synthesis: some chemicals interfere with protein production, disrupting cellular processes

• Immunotoxicity: repeated exposure to a chemical can trigger an immune response.

Explore the intricate relationship between xenobiotics and toxicology in this second lecture. Understand the critical processes of metabolism and excretion, and how they influence the toxicity of various substances. This quiz delves into how foreign substances affect living organisms and the body's methods of handling them.