13: Biochemical and Metabolic Principles

INTRODUCTION

Xenobiotics are compounds that are foreign to a living system. Toxic xenobiotics interfere with critical metabolic processes, causing structural damage to cells or altering their 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.

XENOBIOTIC CHARACTERISTICS AND TOXICITY

The capacity of a xenobiotic to produce injury is affected by many factors, including its absorption, distribution, elimination, site of activation or detoxification, and site of action. This section focuses on how the route of exposure and the ability to cross membranes in order to access particular organs affect toxicity.

The route of exposure to a xenobiotic may confine damage primarily to one organ, for example, pulmonary injury that follows inhalation of an irritant gas or gastrointestinal (GI) injury that follows ingestion of a caustic. 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 containing 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 central nervous system (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 relative 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 result in different clinical effects because they access 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. α-Amanitin is transported into hepatocytes by bile salt transport systems, where inhibition of protein synthesis results in cell death. The electrical charge on a xenobiotic also affects its ability to enter a cell. Unlike the ionized (charged) form of a xenobiotic, the uncharged form is often lipophilic and passes through lipid cell membranes to enter the cells. The pK_a of an acidic xenobiotic (HA↔A⁻ + H⁺) is the pH at which 50% of the molecules are charged (A^– form) and 50% is uncharged (HA form). A xenobiotic with a low pK_a is more likely to be absorbed in an acidic environment where the uncharged form predominates.

GENERAL ENZYME CONCEPTS

The capability to detoxify and eliminate both endogenous toxins and xenobiotics is crucial to the maintenance of physiologic homeostasis. A simple example is the detoxification of cyanide, a potent cellular ...