Metabolismo

ToxicosINTRODUCTION
One of the most important determinants of xenobiotic persistence in the body and
subsequent toxicity to the organism is the extent to which they can be metabolized
and excreted. Several families of metabolic enzymes, often with wide arrays of
substrate specificity, are involved in xenobiotic metabolism. Some of the more important
families of enzymes involved inxenobiotic metabolism include the cytochrome
P450 monooxygenases (CYPs), flavin-containing monooxygenases (FMOs), alcohol
and aldehyde dehydrogenases, amine oxidases, cyclooxygenases, reductases, hydrolases,
and a variety of conjugating enzymes such as glucuronidases, sulfotransferases,
methyltransferases, glutathione transferases, and acetyl transferases.
Most xenobiotic metabolism occurs in theliver, an organ devoted to the synthesis of
many important biologically functional proteins and thus with the capacity to mediate
chemical transformations of xenobiotics. Most xenobiotics that enter the body are
lipophilic, a property that enables them to bind to lipid membranes and be transported
by lipoproteins in the blood. After entrance into the liver, as well as in other organs,xenobiotics may undergo one or two phases of metabolism. In phase I a polar reactive
group is introduced into the molecule rendering it a suitable substrate for phase II
enzymes. Enzymes typically involved in phase I metabolism include the CYPs, FMOs,
and hydrolases, as will be discussed later. Following the addition of a polar group,
conjugating enzymes typically add much more bulky substituents,such as sugars,
sulfates, or amino acids that result in a substantially increased water solubility of the
xenobiotic, making it easily excreted. Although this process is generally a detoxication
sequence, reactive intermediates may be formed that are much more toxic than the
parent compound. It is, however, usually a sequence that increases water solubility
and hence decreases the biologicalhalf life (t0.5) of the xenobiotic in vivo.
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
intoxicationreactions 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.
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112 METABOLISM OF TOXICANTS
7.2 PHASE I REACTIONS
Phase I reactions include microsomal monooxygenations, cytosolic and mitochondrial
oxidations, co-oxidations inthe 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.
7.2.1 The Endoplasmic Reticulum, Microsomal Preparation,
and MonooxygenationsMonooxygenation of xenobiotics are catalyzed either by the cytochrome P450 (CYP)-
dependent monooxygenase system or by flavin-containing monooxygenases (FMO).
Table 7.1 Summary of Some Important Oxidative and Reductive Reactions of Xenobiotics
Enzymes and Reactions Examples
Cytochrome P450
Epoxidation/hydroxylation Aldrin, benzo(a)pyrene, aflatoxin, bromobenzene
N-, O-, S-DealkylationEthylmorphine, atrazine, p-nitroanisole,
methylmercaptan
N-, S-, P-Oxidation Thiobenzamide, chlorpromazine,
2-acetylaminofluorene
Desulfuration Parathion, carbon disulfide
Dehalogenation Carbon tetrachloride, chloroform
Nitro reduction Nitrobenzene
Azo reduction O-Aminoazotoluene
Flavin-containing monooxygenase
N-, S-, P-Oxidation Nicotine, imiprimine, thiourea, methimazole
Desulfuration Fonofos...