Overview of Xenobiotic Metabolism
The driving force in the evolution of sophisticated metabolic detoxification systems was actually fairly straight forward and dependent on the ability of water to act as a “solvent” to dissolve substances.
Since cellular membranes are primarily lipid based and impermeable to most water soluble (scientifically: “polar”) substances, the transport of water-soluble compounds into a cell requires specialized transport proteins. By placing the appropriate transport proteins on the cell membrane, a cell will only allow desirable water-soluble molecules to enter, and will prevent entry of water-soluble toxins. This same paradigm also applies when the cell needs to excrete unwanted water-soluble compounds (like cellular wastes); they exit the cell by a similar mechanism.
In contrast to water-soluble compounds, the lipid cell membrane presents little barrier to lipid-soluble compounds, which can freely pass through it. Potentially damaging lipid-soluble toxins can therefore gain free access to cellular interiors, and are much more difficult to remove.
The metabolic detoxification systems address this problem by converting lipid-soluble toxins into inactive water-soluble metabolites. The “solubilization” of a toxin is accomplished by enzymes which attach (conjugate) additional water-soluble molecules to the lipid-soluble toxin at specific attachment points. If the toxin does not contain any of these attachment points, they are first added by a separate set of enzymes which chemically transform the toxin to include these molecular “handles.” Following the solubilization reactions, the chemically-modified toxin is transported out of the cell and excreted.
These three steps or phases of removing undesirable or harmful lipid-soluble compounds are performed by three sets of cellular proteins or enzymes, called the phase I (transformation) and phase II (conjugation) enzymes, and the phase III (transport) proteins.
Phase I, II, and III metabolisms have different biochemical requirements and respond to different metabolic signals, but must work in unison for proper removal of unwanted xenobiotics (such as toxins or drugs) or endobiotics (such as excess hormones). Enzymes of the phase I, II, and III pathways have several characteristics that make them well suited for their important roles.19 Unlike most other enzymes, detoxification enzymes; can react with many different compounds broadening the number of toxins a single enzyme can metabolize; are more concentrated in areas of the body that are most directly exposed to the environment (like the liver, intestines, or lungs); are inducible, meaning that their synthesis can be increased in response to toxin exposure.
The liver is the primary detoxification organ; it filters blood coming directly from the intestines and prepares toxins for excretion from the body. Significant amounts of detoxification also occur in the intestine, kidney, lungs, and brain, with phase I, II, and III reactions occurring throughout the rest of the body to a lesser degree.