Enzymes drug-acetylating type

Whereas most metabolic change in the human body increases the hydro-philicity of drugs, there are a few cases, admittedly rare, where this property is decreased. Thus, drugs given to lower the lipid content of the bloodstream, if of the type of 4-benzyloxybenzoic acid, unite with Coenzyme A in the liver cytosol. The products, all thioesters, are converted by the enzyme, diglyceride acetyl-transferase, into triglycerides which are simply stored in the body s fat (Fears and Richards, 1981). 

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

As their name implies, the A-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. Examples of this type of reaction are depicted in Figure 4.1. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a... 

One common polymorphism in the United States is for N-acetyltransferase, an enzyme involved in phase II reactions. N-acetyltransferase catalyzes the acetylation of aromatic amines and hydrazines, and other classes of xenobiotics. People characterized as slow acetylators have relatively low N-acetytransf-erase activity. Consequently, slow acetylators are more sensitive to the toxic effects of certain types of drugs, including sulfa drugs. In addition, a study of workers exposed to benzidine in the dye industry suggested a link between the slow acetylator phenotype and the development of bladder cancer. 

A large variety of enzymes and metabolic reactions are presented in Sections 2 and 3. As will become clear, some enzymes catalyze only a single type of reaction (e.g., N-acetylation), whereas others use a basic catalytic mechanism to attack a variety of moieties and produce different types of metabolites (e.g., cytochromes P450). As an introduction to these enzymes and reactions, we present an estimate of their relative importance in drug metabolism (Table 13.4). In this table, the correspondence between the number of substrates... 

The difference between ACh and neostigmine-type drug lies in the much slower (4 x 107 times) rate of hydrolysis of the carbamoylated enzyme (Fig. 8-10B) compared with the acetylated form (Fig. 8-8C). The clinical duration of action of this drug, during which the AChE is presumably unable to process ACh, is 3-4 hours. 

The studies of Klein and Harris (1938) on different tissues of the rabbit indicated that acetylation was perhaps localized to the liver. Blon-dheim (1955) showed, however, that both red cells and white cells of peripheral blood had the capacity to convert sulfanilamide and p-amino-benzoic acid to their acetylated derivatives. With the development of more sensitive assay techniques making use initially of acetyl coenzyme A generating systems, and later of purified preparations of this cosubstrate, enzymic acetylating activity could be demonstrated in many other mammalian tissues. More recently, tissue distribution studies in animals and man have shown that both the pattern and type of arylamine drug-acety-lating activity varies from one tissue to another within an individual and also between individuals (Hearse and Weber, 1970), in support of pro-... 

The amount of this enzyme present in the liver is genetically determined. In some populations, as in Japanese and Eskimo populations, the level is almost never affected— the gene responsible for the slower metabolism is almost absent. However, in other populations, as in African populations, up to 80 percent (four of every five.O have lower levels of this enzyme and could be affected in situations where it is needed to destroy the chemicals in the body. (It should be noted that iproniazid, the example chemical used above, is no longer available in the United States because of other types of toxic side effects it has had on people. However, acetyl-transferase is an enzyme that acts on many different chemicals that are still in use in drug therapy and released into the environment.)... 

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