This Part 2 of our biochemical introduction to drug metabolism [1] presents the redox reactions (oxidations and reductions) and their enzymes. As stated in Part 1, these reactions are clearly the most important ones in drug and xenobiotic metabolism. There are at least three reasons for this state of affairs. First, the biotransformation of a xenobiotic often begins with redox reactions, and particularly reactions catalyzed by cytochromes P450 (abbreviated as CYPs). Second, a vast majority of drugs (and of other xenobiotics, as far as this information is available) are substrates of CYPs [2 -10]. Although any attempt to quantify the total number of marketed drugs, drug candidates, and preclinical candidates that are substrates of human CYPs is but a guess-estimate, a figure of ca. 90% is generally accepted. This percentage is certainly higher when all drug-metabolizing oxidoreductases are taken into account.The third reason for the predominance of redox reactions in drug metabolism is the large diversity of metabolites that may be produced from a single substrate. This diversity involves differences in the chemical nature of the resulting functional groups (chemoselectivity, e.g., a phenolic OH vs. an N-oxido group), as well as positional or stereochemical differences in the creation of a single type of functional group (regioselectivity, e.g., an ortho-vs. a para-phenolic OH, or stereoselectivity, e.g., a cis-vs. trans-alcoholic OH; see Fig. 1.15 in Part 1 [1]). As a first glance of what will be summarized in Part 2, we note here that the metabolites resulting from redox reactions are alcohols, phenols, aldehydes, ketones, carboxylic acids, primary and secondary amines, hydroxylamines, N-oxides, sulfides, sulfoxides or sulfones, to name the major ones. Many of these types of metabolites can be produced by CYP-catalyzed oxidations or reductions. None the less, the contribution of other oxidoreductases should not be underestimated.Some of the reactions catalyzed by CYPs are also carried out (often in parallel on the same substrate) by the flavin-containing monooxygenases (FMOs), another important class of xenobiotic-metabolizing enzymes which will be presented in parallel with the CYPs. Indeed and as we shall see, numerous further oxidoreductases are involved in drug and xenobiotic metabolism [4] [7] [9]. Like CYPs, they can act directly on a foreign substrate or on a metabolite thereof, but none of these oxidoreductases metabolizes as many substrates as CYPs. Still, some of these enzyme systems metabolize a marked number of compounds (e.g., alcohol dehydrogenases) and are

This Part 4 of our biochemical introduction to drug metabolism [1 -4] presents the reactions of conjugation and their enzymes. As we shall see, reactions of conjugation are also a major focus of interest in the metabolism of drugs and other xenobiotics. Books specifically dedicated to conjugation reactions are rare [5], but much recent information can be found in book chapters (e.g.,For a reaction of conjugation to occur, a suitable functional group must be present in the substrate, which will serve as the anchoring site for an endogenous molecule or moiety such as CH 3 , sulfate, glucuronic acid, or glutathione. Conjugation reactions are thus synthetic (i.e., anabolic) reactions whose products are of modestly to markedly higher molecular weight than the corresponding substrate. As for the anchoring group, it can either be present in a xenobiotic or be created by a functionalization reaction. In other words, reactions of conjugation are able to produce first-generation as well as later-generation metabolites. We, therefore, consider as unfelicitous the term of phase II reactions commonly used to designate conjugations.A first issue when discussing reactions of conjugation will be to offer a clear definition. As we shall see, a number of criteria exist, all of which show some degree of fuzziness, and only one of which must necessarily be met. This has indeed led to some confusion with reactions of hydrolysis, which some biochemists have viewed as conjugation. We oppose such a view for reasons previously explained [3]. To repeat what we stated, reactions of hydrolysis are not catalyzed by transferases (EC 2) but by hydrolases (EC 3) [8], and water is not an endogenously synthesized molecule or moiety linked covalently to a cofactor.Reactions of conjugation, like the reactions of functionalization we saw in Parts 2 and 3, act on exogenous substrates (i.e., xenobiotics [1]) as well as endogenous substrates (i.e., endobiotics). This dual functionality may create a potential for metabolic interaction between a drug and an endogenous substrate, a frequently overlooked mechanism of toxicity. Thus, there may be competitive affinity for the catalytic site of an endobiotic-metabolizing enzyme, or there may be competition for the limited supply of a cofactor. A typical example of the latter case is found with

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Drug metabolism as a multidisciplinary science was born in the first half of the 19th century, when hippuric acid (the glycine conjugate of benzoic acid) was discovered in horse urine (hence its name). In 1841, it was discovered in the urine of a human after ingestion of 2 g of benzoic acid, an experiment that marked the beginning of human drug-metabolism studies [1] [2]. Subsequent progress was impressive, but it remained restricted to a narrow circle of biochemists. It was only in the 1950s that drug metabolism really took off due to a convergence of factors including a) the progressive awareness among pharmaceutical scientists of the variety and significance of metabolic reactions, and the involvement of metabolites in unwanted drug effects; b) the groundbreaking studies of distinguished pioneers; c) the explosive development of analytic instrumentation; and d) the acknowledged scientific and didactic impact of a few books [3 -6].Since then, many books have appeared, most of them being edited ones offering expertly written reviews; some such books are listed in the References [7 -20]. Other books were written by one or two authors, their import and tone being more unitarian and didactic (e.g., [21 -28]).The present Work falls in the second category and summarizes the experience of its two authors as lecturers at the M.Sc. and Ph.D. levels. Modern computer technology now allows for lively and attractive teaching support, and we have attempted to transpose an entire course in Powerpoint TM format into a printed format. This was achieved by structuring it into seven Parts (see Fig. 1.1) consisting mainly of colored figures (i.e., the original yet adapted slides), each with an extensive caption, plus a short introductory text, and an extensive bibliography. As a further original feature, the various Parts of the Work are first published as separate review papers before appearing in book form.We hope readers will enjoy these features as much as we enjoyed delivering our lectures and preparing this Work.