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Reactive Metabolites



Between uptake from the environment and excretion from the body, many exogenous compounds (xenobiotics) undergo metabolism to highly reactive intermediates. These metabolites may interact with cellular constituents in numerous ways, such as binding covalently to macromolecules and/or stimulating lipid peroxidation. This biotransformation of relatively inert chemicals to highly reactive intermediary metabolites is commonly referred to as metabolic activation or bioactivation, and it is known to be the initial event in many chemically induced toxicities. Some toxicants are direct acting and require no activation, whereas other chemicals may be activated nonenzymatically. The focus of this chapter, however, is on toxicants requiring metabolic activation and to those processes involved in activation.

In the 1940s and 1950s the pioneering studies of James and Elizabeth Miller provided early evidence for in vivo conversion of chemical carcinogens to reactive metabolites. They found that reactive metabolites of the aminoazo dye N ,N -dimethyl- 4-aminoazobenzene (DAB), a hepatocarcinogen in rats, would bind covalently to proteins and nucleic acids. The term, metabolic activation, was coined by the Millers to describe this process. Moreover they demonstrated that covalent binding of these

chemicals was an essential part of the carcinogenic process.


The overall

scheme of metabolism for potentially toxic xenobiotics is


in Figure 8.1.

As illustrated by this diagram, xenobiotic metabolism can


not only nontoxic metabolites, which are more polar and readily excreted (detoxication), but also highly reactive metabolites, which can interact with vital intracellular macromolecules, resulting in toxicity. In addition reactive metabolites can be detox- ified—for example, by interaction with glutathione. In general, reactive metabolites are electrophiles (molecules containing positive centers). These electrophiles in turn can react with cellular nucleophiles (molecules containing negative centers), such as glutathione, proteins, and nucleic acids. Other reactive metabolites may be free radicals or act as radical generators that interact with oxygen to produce reactive oxygen species that are capable of causing damage to membranes, DNA, and other macromolecules.

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson

ISBN 0-471-26508-X Copyright 2004 John Wiley & Sons, Inc.



Xenobiotic Nontoxic Metabolite Elimination

Reactive Metabolite

Binding to Cellular Molecules (Enzymes, Receptors, Membranes, DNA)


Cellular Repair

(Tissue injury, Cancer,

(DNA repair, Protein

Physiological changes)

synthesis, etc)

Figure 8.1 The relationship between metabolism, activation, detoxication, and toxicity of a chemical.

Although a chemical can be metabolized by several routes, the activation pathway is often a minor route with the remainder of the pathways resulting in detoxication. Activation, however, may become a more dominant pathway in certain situations, thus leading to toxicity. Several examples illustrating these situations are discussed later in this chapter. Some important terms that are often used when discussing activation include parent compound, sometimes referred to as procarcinogen in the case of a carcinogen or prodrug for pharmaceutical compounds; proximate toxic metabolite or proximate carcinogen for one or more of the intermediates; and ultimate toxic metabolite or ultimate carcinogen for the reactive species that binds to macromolecules and DNA.


Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds.

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section.

In addition to activations catalyzed by CYPs and FMOs, phase two conjugations, cooxidation by COX during prostaglandin biosynthesis, and metabolism by intestinal