4.4 Bioactivation and reactive metabolites

Bioactivation transforms seemingly harmless substances into toxic troublemakers. This process, driven by our body's own enzymes, can turn innocent chemicals into reactive bullies that mess with our cells. It's like accidentally creating a monster while trying to clean house.

Understanding bioactivation is crucial for predicting and preventing toxicity. The battle between detoxification and bioactivation determines whether a substance becomes friend or foe. Factors like genetics and enzyme activity influence this delicate balance, making toxicity a highly individual affair.

Metabolic Activation and Reactive Intermediates

Formation and Types of Reactive Intermediates

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• Metabolic activation involves the biotransformation of xenobiotics into more reactive and potentially toxic metabolites
• Electrophiles are electron-deficient molecules that can form covalent bonds with nucleophilic groups in macromolecules (proteins, DNA)
• Free radicals are highly reactive molecules with an unpaired electron that can initiate chain reactions and cause oxidative stress
• Reactive oxygen species (ROS) include superoxide anion, hydrogen peroxide, and hydroxyl radical which can damage cellular components through oxidation
• Reactive intermediate formation occurs during phase I metabolism by cytochrome P450 enzymes, flavin-containing monooxygenases, and other oxidative enzymes

Factors Influencing Reactive Intermediate Formation

• The chemical structure of the xenobiotic determines its susceptibility to metabolic activation (presence of double bonds, aromatic rings)
• The activity and specificity of metabolic enzymes influence the formation of reactive intermediates
  • Genetic polymorphisms in metabolic enzymes can affect an individual's susceptibility to toxicity
  • Induction or inhibition of metabolic enzymes by other xenobiotics can modulate reactive intermediate formation
• The cellular redox status and antioxidant defenses influence the generation and detoxification of reactive intermediates
  • Glutathione (GSH) is a key antioxidant that scavenges reactive intermediates and prevents cellular damage
  • Depletion of GSH can enhance the toxicity of reactive intermediates

Consequences of Bioactivation

Covalent Binding and Cellular Damage

• Covalent binding of reactive intermediates to cellular macromolecules can lead to structural and functional alterations
  • Protein adducts can disrupt enzyme activity, alter cell signaling, and trigger immune responses
  • DNA adducts can cause mutations, strand breaks, and initiate carcinogenesis
• Covalent binding can also deplete cellular antioxidants and disrupt redox homeostasis
• The extent and selectivity of covalent binding determine the severity and specificity of toxicity
  • Acetaminophen (paracetamol) forms a reactive quinone imine that binds to liver proteins and causes hepatotoxicity
  • Aflatoxin B1 forms a reactive epoxide that binds to guanine residues in DNA and initiates liver carcinogenesis

Toxicity Enhancement and Detoxification-Bioactivation Balance

• Bioactivation can enhance the toxicity of xenobiotics by generating more potent and reactive metabolites
  • Benzo[a]pyrene, a polycyclic aromatic hydrocarbon, is bioactivated to a diol epoxide that is more mutagenic and carcinogenic than the parent compound
  • Paraquat, an herbicide, undergoes redox cycling to generate superoxide anion and cause oxidative stress
• The balance between detoxification and bioactivation pathways determines the net toxicity of a xenobiotic
  • Glutathione S-transferases (GSTs) conjugate reactive intermediates with GSH and facilitate their excretion
  • Inhibition of GSTs or depletion of GSH can shift the balance towards bioactivation and enhance toxicity
• Factors that influence the detoxification-bioactivation balance include species differences, genetic polymorphisms, and co-exposure to other xenobiotics
  • Mice are more susceptible to acetaminophen hepatotoxicity than rats due to lower GSH levels and higher bioactivation
  • Individuals with slow acetylator phenotype are more susceptible to isoniazid hepatotoxicity due to reduced detoxification