xenobiotic

• Xenobiotic metabolism


  The set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons
• Xenobiotic metabolism


  • Present in all major groups of organisms
  • Considered to be of ancient origin
  • Often acts to detoxify poisonous compounds
  • Intermediates can themselves be the cause of toxic effects
• Xenobiotic metabolism


  1. Phase I: Enzymes introduce reactive or polar groups into xenobiotics

  2. Phase II: Modified compounds are conjugated to polar compounds

  3. Phase III: Conjugated xenobiotics may be further processed, before being recognized by efflux transporters and pumped out of cells
• Phase I enzymes


  Cytochrome P450 oxidases
• Phase II enzymes


  Transferase enzymes such as glutathione S-transferases
• Xenobiotic metabolism is of particular interest in medicine as part of drug metabolism and as a factor contributing to multidrug resistance in infectious diseases and cancer chemotherapy
• The actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions
• Xenobiotic metabolism of microorganisms is important in environmental science, determining whether a pollutant will be broken down during bioremediation, or persist in the environment
• Ribbon diagram of human cytochrome P450 isozyme 2C9


  • Heme group visible at center
• Permeability barriers and detoxification

  • Organisms are exposed to largely unpredictable and widely varying xenobiotic compounds over time
  • Xenobiotic detoxification systems must be able to remove the almost-limitless number of xenobiotic compounds
  • Solution is a combination of physical barriers and low-specificity enzymatic systems
• Cell membranes


  • Hydrophobic permeability barriers to control access to internal environment
  • Polar compounds cannot diffuse across
  • Uptake of useful molecules is mediated through specific transport proteins
• Diffusion of hydrophobic compounds across cell membranes cannot be controlled, so organisms cannot exclude lipid-soluble xenobiotics using membrane barriers
• Detoxification systems


  • Exploit the hydrophobicity common to membrane-permeable xenobiotics
  • Possess broad substrate specificities to metabolise almost any non-polar compound
  • Useful metabolites are excluded since they are polar and contain charged groups
• Specific enzymes can recognize and remove the reactive by-products of normal metabolism, since these species are derived from normal cellular constituents and usually share their polar characteristics
• Specific detoxification systems


  • Glyoxalase system, which removes the reactive aldehyde methylglyoxal
  • Antioxidant systems that eliminate reactive oxygen species