Chapter 12

Xenobiotics are compounds that are foreign to a living system. Toxic xenobiotics interfere with critical metabolic processes, causing structural damage to cells or altering the cellular genetic material. The specific biochemical sites of actions that disrupt metabolic processes are well characterized for many xenobiotics although mechanisms of cellular injury are not. This chapter reviews the biochemical principles that are relevant to an understanding of the damaging effects of toxic xenobiotics and the biotransformation enzymes and their clinical implications.

The capacity of a xenobiotic to produce injury is affected by many factors including its absorption, distribution, elimination, site of activation or detoxification, site of action, and capability of cross membranes to access a particular organ. Sites of action include the active sites of enzymes, DNA, and lipid membranes. The route of exposure to a xenobiotic may confine damage primarily to one organ, for example, pulmonary injury that follows inhalation or GI injury that follows a caustic ingestion. Hepatocellular injury results when a toxic xenobiotic is delivered to the liver, either by the portal venous system following ingestion or by the hepatic artery carrying blood with xenobiotics absorbed from other sites of exposure. Various factors affect the ability of a xenobiotic to access a particular organ. For example, many potentially toxic xenobiotics fail to produce CNS injury because they cannot cross the blood–brain barrier. The negligible CNS effects of the mercuric salts when compared with organic mercury compounds are related to their inability to penetrate the CNS. Two potent biologic xenobiotics—ricin (from Ricinus communis) and α-amanitin (from Amanita phalloides)—block protein synthesis through the inhibition of RNA polymerase. However, they cause different clinical effects because of access to different tissues. Ricin has a special binding protein that enables it to gain access to the endoplasmic reticulum in GI mucosal cells, where it inhibits cellular protein synthesis and causes severe diarrhea.4 α-Amantin is transported into hepatocytes by bile salt transport systems, where inhibition of protein synthesis results in cell death.50,55 The electrical charge on a toxin also affects its ability to enter a cell. Unlike the ionized (charged) form of a xenobiotic, the uncharged form is lipophilic and passes easily through lipid cell membranes to enter the cells. The pKa of an acidic xenobiotic (HA↔A- + H+) is the pH at which 50% of the molecules are charged (A- form) and 50% are uncharged (HA form). A xenobiotic with a low pKa is more likely to be absorbed in an acidic environment where the uncharged form predominates.

The capability to detoxify and eliminate both endogenous toxins and xenobiotics is crucial to the maintenance of physiologic homeostasis and normal metabolic functions. A simple example is the detoxification of cyanide, a potent cellular poison that is common in the environment and is also a product of normal metabolism. Mammals have evolved the enzyme rhodanese, which combines cyanide with thiosulfate to create the less toxic, renally ...

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