Metabohsm

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

A broader view would include the addition of a substrate to stimulate the growth of organisms known to degrade the contaminant of interest only as an incidental part of their metaboHsm, one might almost say serendipitously. This process is sometimes called co-metaboHsm, and it too has had success. 

Triazines pose rather more of a problem, probably because the carbons are in an effectively oxidized state so that no metaboHc energy is obtained by their metaboHsm. Very few pure cultures of microorganisms are able to degrade triazines such as Atrazine, although some Pseudomonads are able to use the compound as sole source of nitrogen in the presence of citrate or other simple carbon substrates. The initial reactions seem to be the removal of the ethyl or isopropyl substituents on the ring (41), followed by complete mineralization of the triazine ring. 

Carbamates such as Aldicarb undergo degradation under both aerobic and anaerobic conditions. Indeed the oxidation of the sulfur moiety to the sulfoxide and sulfone is part of the activation of the compound to its most potent form. Subsequent aerobic metaboHsm can completely mineralize the compound, although this process is usually relatively slow so that it is an effective iasecticide, acaricide and nematocide. Anaerobically these compounds are hydrolyzed, and then mineralized by methanogens (61). 

For those dmgs that are administered as the racemate, each enantiomer needs to be monitored separately yet simultaneously, since metaboHsm, excretion or clearance maybe radically different for the two enantiomers. Further complicating dmg profiles for chiral dmgs is that often the pharmacodynamics and pharmacokinetics of the racemic dmg is not just the sum of the profiles of the individual enantiomers. 

The majoi metabolic tiansformations of the adienal-coitical hormones generally foUow the metabohsm of cortisol, which undergoes the following conversions in vitro ... 

A.- ng deduction. This is an irreversible reaction which is a foremost determinant of the secretion rate of cortisol (double bonds and C-3 carbonyl). Catalyzed predominantiy by cortisone P-reductase and 3a-hydroxysteroid dehydrogenases, SP sterols result, although 5a sterols are more prevalent in the case of other glucocorticoids. Urocortisol and urocortisone result from the metabohsm of cortisol and cortisone, respectively. Compounds can be complexed to glucuronic acid at this point. 

C-20 deduction. Two stereoisomers can result from this transformation, although cortisol is thought to act primarily with (R)20P-hydroxysteroid dehydrogenase. This is a first step in the metabohsm of corticosterone. 

Compounds having the 16,17 ketal, eg, budesonide, amcinonide, fluocinonide, halcinonide, triamcinolone acetonide, and flurandrenohde, also undergo metabohsm by routes that parahel that of cortisol metabohsm. Unsymmetrical acetals such as budesonide are also metabolized by routes not available to the more metabohcahy stable symmetrical 16a,17a-isopropyhdiene-dioxysubstituted compounds (desonide, flunisohde, and triamcinolone acetonide). Isozymes within the cytochrome P450 3A subfamily are thought to catalyze the metabohsm of budesonide, resulting in formation of 16a-hydroxyprednisolone and 6P-hydroxybudesonide (19,20) (Fig. 3) in addition to the more common metabohc steps (oxidation via reduction of A, etc). 

Ketopregnan-21-oic Acids, the 17(3-Carboxy Androstanes, and the D-Homocorticoids. In the course of studies on the metabohsm of fluocoitolone (103) the formation of the water-soluble carboxyhc acid (105, R = H) was reported. As a free 21-hydroxyl is not necessary for antiinflammatory activity, it was concluded that the esters (105, R = alkyl) of the preceding metabohte would possess antiinflammatory activity on topical administration but would be devoid of systemic activity when hydrolysis to the free acid occurs followed by... 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The propensity of nitriles to release cyanide subsequent to metaboHsm is the basis of their acute toxicity. Nitriles that form tertiary radicals at their alpha carbon atoms (eg, isobutyronitrile, 2-methylbutyronitrile) are substantially more acutely lethal than nitriles that form secondary radicals at their alpha carbons (eg, butyronitrile, propionitnle). Cyanohydrins are acutely toxic because they are unstable and release cyanide quickly. Alpha-aminonitriles are also acutely toxic, presumably by analogy with cyanohydrins. 

Biochemistry resulted from the early elucidation of the pathway of enzymatic conversion of glucose to ethanol by yeasts and its relation to carbohydrate metaboHsm in animals. The word enzyme means "in yeast," and the earfler word ferment has an obvious connection. Partly because of the importance of wine and related products and partly because yeasts are relatively easily studied, yeasts and fermentation were important in early scientific development and stiU figure widely in studies of biochemical mechanisms, genetic control, cell characteristics, etc. Fermentation yeast was the first eukaryote to have its genome elucidated. 

Acrylonitrile is beheved to behave similarly to hydrogen cyanide (enzyme inhibition of cellular metaboHsm) (150) and is befleved to be a potential carcinogen (151). It can also affect the cardiovascular system and kidney and Hver functions (150). Eurther information on the toxicology and human exposure to acrylonitrile is available (152—154) (see Acrylonitrile). 

Early investigators grouped alkaloids according to the plant families in which they are found, the stmctural types based on their carbon framework, or their principal heterocycHc nuclei. However, as it became clear that the alkaloids, as secondary metaboUtes (30—32), were derived from compounds of primary metabohsm (eg, amino acids or carbohydrates), biogenetic hypotheses evolved to link the more elaborate skeletons of alkaloids with their simpler proposed pregenitors (33). These hypotheses continue to serve as valuable organizational tools (7,34,35). 

Phenylalanine- and Tyrosine-Derived Alkaloids. Carbohydrate metaboHsm leads via a seven-carbon sugar, ie, a heptulose, derivative to shikimic acid [138-59-0] (57), C H qO, which leads in turn to prephenic acid [126-49-8] (58), (43). 

In milk fat, cholesterol is associated with Hpoproteins in the milk fat globule. It is also a component of animal membranes and controls rigidity and permeabihty of the membranes. Cholesterol has interesting surface properties and can occur in Hquid crystalline forms. Plants contain sterols such as P-sitosterol [83-46-5] (4b) or stigmasterol [83-48-7] (4c). Their functions in plant metaboHsm are not yet well understood. Analysis of sterols has proven useful for detection of adulteration of edible fats (9). 

Lipids present in the diet may become rancid. When fed at high (>4-6%) levels, Hpids may decrease diet acceptabiUty, increase handling problems, result in poor pellet quaUty, cause diarrhea, reduce feed intake, and decrease fiber digestion in the mmen (5). To alleviate the fiber digestion problem, calcium soaps or prilled free fatty acids have been developed to escape mminal fermentation. These fatty acids then are available for absorption from the small intestine (5). Feeding whole oilseeds also has alleviated some of the problems caused by feeding Hpids. A detailed discussion of Hpid metaboHsm by mminants can be found (16). 

E. J. Largent, "MetaboHsm of Inorganic Fluoride" ia Fluoridation as a Public Health Measure, American Association for the Advancement of Science, Washiagton, D.C., 1954, pp. 49—78. 

E. N. Dost and co-workers, "MetaboHsm and Pharmacology of Inorganic and Eluorine Containing Compounds," Final Report (July 1, 1964—June 30, 1967), AMRL-TR-67-224 (AD 681-161), Contract AE 33(615)-1799, Oregon State University, CorvaUis, Oreg., Aug. 1968. 

Rats exposed to 500 ppm of bromotrifluoroethylene died following a 4-h exposure. Since the monomer decomposes in air, the level of exposure to it was actually lower. The effects in rats of repeated exposure over a two-week period have been studied. At 50 ppm, the animals lost weight and renal damage was noted although the effect was reversible. Very mild testicular damage was seen at 50 but not 10 ppm. The amount of urinary duotide excreted suggested that extensive metaboHsm was occurring (34). 

Urethane [51-79-6] (ethyl carbamate) occurs as a natural by-product in fermented products such as wine, Hquors, yogurt, beer, bread, oHves, cheeses, and soy sauces. Whereas urethane has a known cancer etiology in experimental animals, no such relationship has yet been proven in humans (108,109). Alcohol may act by blocking the metaboHsm of urethane, and thus exert a protective effect in humans consuming alcohoHc beverages (110). 

Pseudomonads also have the abiUty for xenobiotic metaboHsm and are capable of carrying out diverse sets of chemical reactions. Pseudomonas species is used ia the commercial productioa of acrylamide (qv) (18). Several operoas iavolved ia the metaboHsm of xeaobiotic compouads have beea studied. Use of Pseudomonads for the clean up of the environment and for the production of novel chemical iatermediates is likely to be an area of active research ia the 1990s. 

The growth of animals can be defined as an increase in mass of whole body, tissue(s), organ(s), or ceU(s) with time. This type of growth can be characterized by morphometric measurements eg, skeletal muscle or adipose tissue growth can be described by observing temporal changes in ceU number, ie, hyperplasia, and ceU size, ie, hypertrophy. Growth also includes developmental aspects of function and metaboHsm of cells and tissues from conception to maturity. 

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