Hydroxylation and metabolism

As a rule metabolic hydroxylation of an active compound represents a detoxication (phase I) mechanism. It results 

FIGURE 20.41 Structure and binding affinity of 3-quinolinecarboxam-ides to human endogenous NKl receptor in UCl IMG cells.  

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While the hydrocarbon fraction of insect cuticular lipids is certainly the most studied and has been shown to play a key role in a wide range of chemical communication, other lipids are often present on the surface of insects. The most common cuticular lipids in addition to hydrocarbons include a variety of types of esters, free fatty acids, primary and secondary alcohols, ketones and sterols. Triacylglycerols and the more polar phospholipids are not common components of insect cuticular lipids. In some cases, hydrocarbons are hydroxylated and metabolized to oxygenated components, and these products include some of the short range and contact pheromones of the housefly (Blomquist, 2003) and the German cockroach (Schal et al., 2003). The oxygenated cuticular lipids are discussed in Chapter 9 (Buckner, this book). 

M. domestica also hydroxylates and metabolizes alkenes and alkanes to oxygenated derivatives. The epoxide and ketone derivative of (Z)-9-tricosene, (9,10)-epoxytricosane and (Z)-14-tricosene-10-one are derived from the C23 alkene by a cytochrome P450 enzyme which epoxidizes at the 9,10 position and hydroxylates at carbon 10 from the other end of the molecule, and the secondary alcohol is then oxidized to the ketone (Ahmad et al., 1987). 

Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydrox5dryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOa), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid...

Blattmann has also suggested an alternative pathway which involves a terminal oxidation of the chain after 3-hydroxylation and has presented data for the metabolism of 2-hydroxybutylbutylnitros-amine indicating that this does occur. ... 

It has become clear that benzoate occupies a central position in the anaerobic degradation of both phenols and alkylated arenes such as toluene and xylenes, and that carboxylation, hydroxylation, and reductive dehydroxylation are important reactions for phenols that are discussed in Part 4 of this chapter. The simplest examples include alkylated benzenes, products from the carboxylation of napthalene and phenanthrene (Zhang and Young 1997), the decarboxylation of o-, m-, and p-phthalate under denitrifying conditions (Nozawa and Maruyama 1988), and the metabolism of phenols and anilines by carboxylation. Further illustrative examples include the following ... 

Compared with monocyclic aromatic hydrocarbons and the five-membered azaarenes, the pathways used for the degradation of pyridines are less uniform, and this is consistent with the differences in electronic structure and thereby their chemical reactivity. For pyridines, both hydroxylation and dioxygenation that is typical of aromatic compounds have been observed, although these are often accompanied by reduction of one or more of the double bonds in the pyridine ring. Examples are used to illustrate the metabolic possibilities. 

Eto M, Casida JE, Eto T. 1962. Hydroxylation and cyclization reactions involved in the metabolism of tri-ort/20-cresyl phosphate. Biochem Pharmacol 11 337-352. 

UDP-glucuronyltransferases catalyze the addition of glucuronic acid onto phenol, hydroxyl and carboxylic acid functions of molecules. They are expressed in many tissues of the body, including the liver and intestine [2-5], Microsomes from human intestines have been shown to metabolize UDP-glucuronyltransferase substrates including p-nitrophenol [6], 1-naphthol, morphine, and ethinylestradiol [4]. The relative rates of metabolism of these substrates in liver and intestinal microsomes are shown in Table 13.1. 

Acetyltransferases catalyze the acetylation of amino, hydroxyl, and thiol functional groups. Acetylation of hydroxy and thiol groups is comparatively rare and of much less importance in alkaloid metabolism than reactions with amino functional groups. The types of amines that are acetylated include arylamines (the major route of metabolism in many species), aliphatic amines, hydrazines, sulfonamides, and the a-amino group of cysteine conjugates. The purification, physical properties, and specificity of the N-acetyltransfereases have been reviewed (116-118). 

There is no experimental evidence adequate to evaluate whether metabolism of M-hcxanc is different in children. Similarly, there is no information available from animal experiments. The initial step in -hexane metabolism in animals is a hydroxylation step catalyzed by a P-450 enzyme. Since some of these enzymes are developmentally regulated, it would be of interest to know (1) if there are specific P-450 isozymes involved in -hexane hydroxylation and, (2) if so, are these isozymes known to be developmentally regulated ... 

Iida, I., Miyata, A., Arai, M., Hirota, M., Akimoto, M., Higuchi, S., Kobayashi, K. and Chiba, K. (2004) Catalytic roles of CYP2C9 and its variants (CYP2C9 2 and CYP2C9 3) in lomoxicam 5 -hydroxylation. Drug Metabolism... 

Hydrolytic cleavage plays an important role in the metabolic fate of both carbromal (4.210) and bromisoval (4.213). A product of hydrolysis of carbro-mal, 2-bromo-2-ethylbutyramide (4.211), was isolated from the urine of patients intoxicated with carbromal as well as from the urine of rats, mice, and dogs dosed with the drug [138], A suspected further metabolite is 2-bromo-2-ethylbutyric acid (4.212). Other metabolic transformations of carbromal involve hydroxylation and debromination. 

Little is known on the metabolic fate of l-methylpyrrolidin-2-one (5.60), an industrial solvent also useful as a solubilizing agent and a penetration enhancer in topical formulations. A preliminary investigation of the disposition and metabolism of labeled l-methylpyrrolidin-2-one in the rat showed that the compound is excreted mainly in urine [171]. Three urinary metabolites were detected, the major of which (ca. 15% of the dose) was 4-(methylami-no)but-2-enoic acid (5.61). This unsaturated product may likely have been formed by H20 elimination from a hydroxylated metabolite. 

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