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Xenobiotic Metabolism Fundamentals

Xenobiotics are molecules that are introduced into the body from the environment and subsequently metabolized by the body. Most pharmacological agents are lipophilic and their elimination from the body is facilitated by enzymatic modifications to render them more hydrophilic. The liver is a major site for xenobiotic metabolism. In addition to foreign substances, a number of endogenous substances, including some eicosanoids and steroid hormones, are also modified to facilitate their excretion. Hence, the enzymes and pathways described in this section have strong ties to many of the pathways described in prior sections.

Xenobiotic metabolism strongly impacts the body’s oxidative status (see figure below).Cytochrome P450 mediated reactions generate significant levels of reactive oxygen species (ROS) and are key to the toxicity of many xenobiotics. Glutathione transferases reduce the cell’s reserves of glutathione, the major intracellular antioxidant. Also illustrated is the ability of xenobiotics to modulate (e.g. via the Ah receptor) the expression of drug metabolizing enzymes, and the role of transport proteins in exporting unmodified or conjugated xenobiotics from the cell. The products described herein are focused on a few of the key players in xenobiotic metabolism: the cytochromes P450, Glutathione Transferases and Glyoxalases.