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Biotransformation Sites
Biotransforming enzymes are widely distributed throughout the body. However, the liver is the primary biotransforming organ due to its large size and high concentration of biotransforming enzymes. The kidneys and lungs are next with 10-30% of the liver's capacity. A low capacity exists in the skin, intestines, testes, and placenta. Since the liver is the primary site for biotransformation, it is also potentially quite vulnerable to the toxic action of a xenobiotic that is activated to a more toxic compound.
Within the liver cell, the primary subcellular components that contain the transforming enzymes are the microsomes (small vesicles) of the endoplasmic reticulum and the soluble fraction of the cytoplasm (cytosol). The mitochondria, nuclei, and lysosomes contain a small level of transforming activity.
Microsomal enzymes are associated with most Phase I reactions. Glucuronidation enzymes, however, are contained in microsomes. Cytosolic enzymes are non-membrane-bound and occur free within the cytoplasm. They are generally associated with Phase II reactions, although some oxidation and reduction enzymes are contained in the cytosol. The most important enzyme system involved in Phase I reactions it the cytochrome P-450 enzyme system. This system is frequently referred to as the "mixed function oxidase (MFO) " system. It is found in microsomes and is responsible for oxidation reactions of a wide array of chemicals.
The fact that the liver biotransforms most xenobiotics and that it receives blood directly from the gastrointestinal tract renders it particularly susceptible to damage by ingested toxicants. Blood leaving the gastrointestinal tract does not directly flow into the general circulatory system. Instead, it flows into the liver first via the portal vein. This is known as the "first pass" phenomena. Blood leaving the liver is eventually distributed to all other areas of the body; however, much of the absorbed xenobiotic has undergone detoxication or bioactivation. Thus, the liver may have removed most of the potentially toxic chemical. On the other hand, some toxic metabolites are in high concentration in the liver.
 
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