Xenobiotic metabolism hydrolysis reactions

Non-redox reactions where water is formed as a product are reactions of dehydration. Such reactions can occur between two substrate molecules, or they can involve two functional groups in a single substrate, either creating a new bond (e.g., lactone formation), or transforming a single into a double bond. In xenobiotic metabolism, dehydration is usually in dynamic equilibrium with hydrolysis or hydration and is of relatively modest significance (Chapt. 11). 

Examples of oxidative reactions are shown in Table 3.3. Generally, reduction and hydrolysis reactions play subordinate roles in xenobiotic metabolism compared to oxidation reactions. Examples of reduction and hydrolysis reactions are shown in Tables 3.4 and 3.5, respectively. To reiterate the net result of phase I reactions is the... 

Intestinal microflora are capable of impacting xenobiotic metabolism by causing enterohepatic circulation and delayed excretion and by catalyzing many of the reactions that also occur as a result of detoxication and bioactivation reactions by phase I and II enzymes. The carbohydrate amygdalin, which contains a cyanide substituent, is found in the kernels of various fruits including plum, cherry, peach, and apricot as well as in almonds. Hydrolysis by the [f-glucosidases in intestinal bacteria yields reactive intermediates capable of releasing cyanide. 

When certain xenobiotics, including esters and amides, are administered to animals they are hydrolyzed. Hydrolysis reactions are important for the sequential metabolism of chemicals converted to epoxides by the P450 system. These reactions are classified as phase I because they free up functional groups (e.g., COOH, NH2, OH, — SH, and — SO3H) that are important sites for conjugation (phase II) reactions. 

The process of xenobiotic metabolism contains two phases commonly known as Phase I and Phase II. The major reactions included in Phase I are oxidation, reduction, and hydrolysis, as shown in Figure 10.1. Among the representative oxidation reactions are hydroxylation, dealkylation, deamination, and sulfoxide formation, whereas reduction reactions include azo reduction and addition of hydrogen. Such reactions as splitting of ester and amide bonds are common in hydrolysis. During Phase I, a chemical may acquire a reaction group such as OH, NH2, COOH, or SH. 

The liver is the principal organ responsible for xenobiotic metabolism. One of its major roles is to convert lipophilic nonpolar molecules to more polar water-soluble forms. The drug molecule (a xenobiotic) can be modified by phase I reactions, which alter chemical structure by oxidation, reduction, or hydrolysis or by phase II reactions, which conjugate the drug (glucuronidation or sulfation) to create more water-soluble forms. Typically, both phase I and phase II reactions occur. Most drug metaboHsm takes place in the microsomal fraction of the hepatocytes, where many environmental chemicals and endogenous biochemicals (xeno-biotics) are also processed by the same mechanisms. 

The pathways ot xenobiotic metabolism are divided into two major categories. Phase 1 reactions (biotranstormations) include oxidation, hydroxylation, reduction, and hydrolysis. In these enzymatic reactions, a new functional group Is Introduced Into the substrate molecule, an existing functional group is modified, or a functional group or acceptor site tor Phase 2 transfer reactions Is exposed, thus making the xenobiotic more polar and, therefore, more readily excreted. 

Biotransformation refers to changes in xenobiotic compounds as a result of enzyme action. Reactions not mediated by enzymes may also be important. As examples of nonenzymatic transformations, some xenobiotic compounds bond with endogenous biochemical species without an enzyme catalyst, undergo hydrolysis in body fluid media, or undergo oxidation-reduction processes. However, the metabolic phase I and phase II reactions of xenobiotics discussed here are enzymatic. 

Many xenobiotics contain alkyl groups, such as the methyl (-CH3) group, attached to atoms of O, N, and S. An important step in the metabolism of many of these compounds is replacement of alkyl groups by H, as shown in Figure 7.6. These reactions are carried out by mixed-function oxidase enzyme systems. Examples of these kinds of reactions with xenobiotics include O-dealky-lation of methoxychlor insecticides, N-dealkylation of carbary 1 insecticide, and S-dealkylation of dimethyl mercaptan. Organophosphate esters (see Chapter 18) also undergo hydrolysis, as shown in Reaction 7.3.12 for the plant systemic insecticide demeton ... 

Rich in both phase I (principally the cytochromes P450, catalyzing hydrolysis, reduction, and oxidation reactions) and phase II (catalyzing conjugation of xenobiotic molecules with hydrophilic moieties) biotransforming enzymes, the liver is the metabolic center of the body. In fact, most of the field of biochemistry is concerned with its metabolic reactions. The liver essentially converts ingested food into a balanced cell culture medium via metabolic interconversion of amino acids, carbohydrates, and lipids and synthesizes many substances that are subsequently exported for use in other areas of... 

In addition to their filtration function, the kidneys are also metabolically active and carry out extensive oxidation, reduction, hydrolysis, and conjugation reactions, with enzymes similar to those present in the liver and other extrarenal tissues involved in these metabolic reactions, f0 As noted previously, metabolites of xenobiotics are often toxic than the parent compounds. As a result of the combination of the filtration and metabolic functions, the kidneys are targets for many toxic chemicals. 

These additional metabolic processes may not significantly stabilize the 0-1 glucose ester bond from non-enzymatlc hydrolysis, but they may block enzymatic processes such as B-glucosldase hydrolysis or the reverse reaction in the synthesis of the 0-glucose ester. Thus, the formation of these more complex metabolites may result in detoxification of the xenobiotic. 

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