Metabolism of toxicants

Phase I monooxygenations are more likely to form reactive intermediates than phase II metabolism because the products are usually potent electrophiles capable of reacting with nucleophilic substituents on macromolecules, unless detoxified by some subsequent reaction. In the following discussion, examples of both detoxication and intoxication reactions are given, although greater emphasis on activation products is provided in Chapter 8. 

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley Sons, Inc. 

Phase I reactions include microsomal monooxygenations, cytosolic and mitochondrial oxidations, co-oxidations in the prostaglandin synthetase reaction, reductions, hydrolyses, and epoxide hydration. All of these reactions, with the exception of reductions, introduce polar groups to the molecule that, in most cases, can be conjugated during phase II metabolism. The major phase I reactions are summarized in Table 7.1. 

Monooxygenation of xenobiotics are catalyzed either by the cytochrome P450 (CYP)-dependent monooxygenase system or by flavin-containing monooxygenases (FMO). 

Epoxidation/hydroxylation Aldrin, benzo(a)pyrene, aflatoxin, bromobenzene 

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Allison, M. J. (1978). The role of ruminal microbes in the metabolism of toxic constituents from plants. In Effects of Poisonous Plants on Livestock, ed. R. F. Keeler, K. R. Van Kampen, and L. J. James, pp. 101-118. New York Academic Press. 

Altitude. Altitude can either increase or decrease toxicity. It has been suggested that these effects are related to the metabolism of toxicants rather than to physiological mechanisms involving the receptor system, but in most examples this has not been demonstrated clearly. Examples of altitude effects include the observations that at altitudes of > 5000 ft, the lethality of digitalis or strychnine to mice is decreased, whereas that of D-amphetamine is increased. 

Hodgson, E., and J. A. Goldstein. Metabolism of toxicants Phase I reactions and pharmacogenetics. In Introduction to Biochemical Toxicology, 3rd ed., E. Hodgson, R. C. Smart, eds., New York Wiley, 2001. 

Metabolism is especially important in toxicological chemistry for two reasons (1) interference with metabolism is a major mode of toxic action, and (2) toxic substances are transformed by metabolic processes to other materials that are usually, though not invariably, less toxic and more readily eliminated from the organism. This chapter introduces the topic of metabolism in general. Specific aspects of the metabolism of toxic substances are discussed in Chapter 7. 

Metabolism is of utmost importance in toxicity. Details of the metabolism of toxic substances and their precursors are addressed in Chapter 7, Toxicological Chemistry. At this point it should be noted that there are several major aspects of the relationship between toxic substances and... 

Biotransformation may also lead to deviations from EP, but this process is not well studied. Biotransformation is the uptake and metabolism of toxicants that usually results in more water-soluble metabolites. Especially when the exchange with the pore water is slow, even low levels of transformation may affect the internal exposure to the parent compound. 

MICROSOME A phospholipid-nucleoprotein complex derived from the ribosomes and endoplasmic reticulum of eukaryotic cells site of diverse enzymatic reactions important in the metabolism of toxicants and other chemicals. 

Reisfeld B, Yang RSH. 2004. A reaction network model for CYP2E1-mediated metabolism of toxicant mixtures. Environ Toxicol Pharmacol 18 173-179. 

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