Metabolizing system

These chemical effects become important in medicine because living systems operate mostly through the reactions of enzymes, which catalyze all sorts of metabolic reactions but are very sensitive to small changes in their environment. Such sensitivity can lead to preferential absorption of some deleterious isotopes in place of the more normal, beneficial ones. One example in metabolic systems can be found in the incorporation of a radioactive strontium isotope in place of calcium. 

Special isotope ratio mass spectrometers are needed to measure the small variations, which are too small to be read off from a spectrum obtained on a routine mass spectrometer. Ratios of isotopes measured very accurately (usually as 0/00, i.e., as parts per 1000 [mil] rather than parts per 100 [percent]) give information on, for example, reaction mechanisms, dating of historic samples, or testing for drugs in metabolic systems. Such uses are illustrated in the main text. 

The hver microsomal dmg-metabolizing system is of particular importance. This oxidative pathway is mediated by isozymes of the cytochrome family (Fig. 4). At least ten enzyme families exist to accommodate the abiUty of humans to handle many foreign molecules (21). 

Physiological Role of Citric Acid. Citric acid occurs ia the terminal oxidative metabolic system of virtually all organisms. This oxidative metabohc system (Fig. 2), variously called the Krebs cycle (for its discoverer, H. A. Krebs), the tricarboxyUc acid cycle, or the citric acid cycle, is a metaboHc cycle involving the conversion of carbohydrates, fats, or proteins to carbon dioxide and water. This cycle releases energy necessary for an organism s growth, movement, luminescence, chemosynthesis, and reproduction. The cycle also provides the carbon-containing materials from which cells synthesize amino acids and fats. Many yeasts, molds, and bacteria conduct the citric acid cycle, and can be selected for thek abiUty to maximize citric acid production in the process. This is the basis for the efficient commercial fermentation processes used today to produce citric acid. 

It is obvious that rapid metabolite production requires high fluxes of carbon through the metabolic systems responsible for its synthesis. The rate of metabolite production, for a wide range of micro-organisms, has been shown to increase with decrease in... 

All living spedes are able to synthesise amino adds. Many spedes, however, are defident in their ability to synthesise within their own metabolic system all the amino acids necessary for life. The eight amino acids with this spedal significance for file human species are called essential amino adds, these are ... 

Center for Modeling Integrated Metabolic Systems (MIMS), http //www.csuohio. edu/mims/ (accessed October 1, 2005)... 

SOHN O S, SURACE A, FIALA E S, RICHIE J P, COLOSIMO S, ZANG E and WEISBURGER J H (1994) Effects of green and black tea on hepatic xenobiotic metabolizing systems in the male F344 mt , Xenobiotica, 24, 119-27. 

The third study has employed 4,6-dinitrobenzofuroxan and as metabolic systems the one-electron reductants NADPHxytochrome P450 reductase and ferredoxin NADP(+) reductase and the two-electron reductants DT-diaphorase and Enterobacter cloacae nitroreductase [239]. The compound is activated either by DT-diaphorase or nitroreductase. 

Besides the metabolic system of living and growing eukaryotes, the use of prokaryotes in industrial production of pharmaceutical precursors by fermentation is a common strategy [9,10]. Here, the cmcial steps are the inocula preparation to reach reproducible yields and the... 

Among common in vitro metabolizing systems, liver microsomes and liver S9 fractions are used more often in metabolite synthesis than other systems. The majority of drug metabolism is mediated by CYPs [8]. Liver microsomes contain a high concentration of CYPs and other... 

The reduction potential must suffice for all the reduction reactions involved in the metabolic system (Wachtershauser, 1992). 

The results obtained appeared quite promising, but the real sensation was the detection of pyruvate, the salt of 2-oxopropanoic acid (pyruvic acid), which is one of the most important substances in contemporary metabolism. Pyruvic acid was first obtained in 1835 by Berzelius from dry distillation of tartaric acid. The labile pyruvate was detected in a reaction mixture containing pure FeS, 1-nonanethiol and formic acid, using simulated hydrothermal conditions (523 K, 200 MPa). The pyruvate yield, 0.7%, was certainly not overwhelming, but still remarkable under the extreme conditions used, and its formation supports Wachtershauser s theory. Cody concludes from these results that life first evolved in a metabolic system prior to the development of replication processes. 

Schuetz EG, Schinkel AH. Drug disposition as determined by the interplay between drug-transporting and drug-metabolizing systems. J Biochem Mol Toxicol 1999 13[3—4] 219—222. 

Measurements of gene expression or protein abundance, which are often favored in metabolic engineering, do not necessarily provide a route to understand what is occurring within metabolic systems. 

Another study by McChesney and co-workers on the metabolism of nalidixic acid in the immature calf(23) demonstrated a pattern of metabolism very different than in man. The half-life of nalidixic acid was found to be about 24 hours and a large amount was excreted into the feces. The immature calves were also unable to excrete nalidixic acid into the urine at concentrations greater than found in the plasma and conjugated drug was present at low levels only. Calves seven months old had metabolic patterns much closer to man the plasma half-life was about 1.5 hours, the concentration of excretion into the urine was at least ten times that in plasma and the extent of conjugation was increased. The inability to metabolize nalidixic acid by the immature calf was considered to be due to incomplete development of its metabolic system. 

All of the principles and ideas covered in the previous section may be translated directly to the use of microorganisms as tools in the production of compounds of plant biosynthetic or biodegradative importance. Just as one finds microbial systems to be of value in preparing metabolites in mammalian systems, it may be possible to use microbial transformations to prepare derivatives of alkaloids that might be found rarely or only in very small quantities in plants. In this way, abundant prototype alkaloids may be used as microbial transformation substrates to provide a range of metabolites. As in the mammalian case, metabolism studies using plant tissues, tissue cultures, or cell-free extracts may be conducted in parallel with microbial metabolic systems. Metabolites common to both would be prepared in quantity by relatively simple fermentation scale-up methods. 

The subject of metabolism of tetrahydroisoquinolines and related alkaloids in mammalian metabolic systems has recently been reviewed (205, 206). The formation of biogenic amine-derived alkaloids in mammals and their transformation by O-methylation reactions have been described. 

Some of these problems can be overcome by the use of cell-based systems, in particular, primary hepatocytes. Hepatocytes closely simulate the metabolic systems found in the intact fiver and do not require additional cofactors for optimal enzyme activity. However, apart from greater technical difficulties in obtaining hepatocytes as opposed to S9 fraction, hepatocytes can effectively detoxify particular carcinogens and prevent their detection as mutagens. Despite these difficulties, hepatocytes have a role to play in mutagenicity screening, in both bacterial and mammalian-based systems (Tweats and Gatehouse, 1988). 

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