The roles of metabolism

In Section S.l it is stated that the main purpose of a living system is to ensure its survival and reproduction. This is achieved through the chemistry of the cell and there are two primary activities. 

Enzymes are organised into metabolic pathways which collectively constitute metabolism. Two types of metabolism are found in cells, catabolism (breakdown pathways) and anabolism (synthetic pathways). Linking these two types of metabolic reactions are the intermediary reactions of central metabolism. Cells, which contain many complex polymers, thus have the means to generate and convert monomeric materials into the complex biological structure. The sources of these materials are the simpler components from the cell s environment, such as inorganic salts and glucose (Fig. 5.9). 

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Turner, G.R. Tartakoff, A.M. (1989). The response of the Golgi complex to microtubule alterations The roles of metabolic energy and membrane traffic in Golgi complex organization. J. Cell Biol. 109,2081-2088. 

Buben JA, O Flaherty EJ. 1985. Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene A dose-effect study. Toxicol Appl Pharmacol 78 105-122. 

D. The Role of Metabolism and Intestinal Secretion Reaction-Transport Coupling... 

Nielsen, J. (1998) The role of metabolic engineering in the production of secondary metabolites. Current Opinion in Microbiology, 1, 330—336. 

Park, B.K. et al. 2005. The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45 177. 

Primary hepatocyte cultures have been used in vitro to metabolically activate toxins for evaluation with target tissues. Cocultures of rat embryos with hepatocytes have been used to study the role of metabolism in teratogenesis (Oglesby et al., 1986). Lindahl-Kiessling et al., (1989), in an attempt to bring test conditions closer to in vivo conditions, developed an assay utilizing primary rat hepatocytes and human peripheral lymphocytes to detect metabolism-mediated mutagenesis. 

Eavigne JG, Marchand C. 1974. The role of metabolism in chloroform hepatotoxicity. Toxicol Appl Pharmacol 29 312-326. 

Thompson, T. N. Early ADME in support of drug discovery the role of metabolic stability studies. Curr Drug Metab 2000, 1, 215-241. 

Kaminski NE, Stevens WD. 1992. The role of metabolism in carbon tetrachloride-mediated immunosuppression, /r v/fro studies. Toxicology 75 175-188. 

Lemberger, L., McMahon, R., and Archer, R. The role of metabolic conversion on the mechanism of action of cannablnolds. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York Raven Press. 1 125-132, 1976. 

A combined in vivolin vitro system for chemical metabolites has been developed that demonstrates the role of metabolism in activating compounds. In this system, rats are treated with a chemical and serum is removed 1 h later and cultured with explanted embryos. This system has been used to demonstrate that metabolites of procarbazine are toxic to explanted embryos, but that procarbazine and a microsomal preparation are not toxic to explanted embryos grown in culture medium (Schmid et al., 1982). 

Depending on the role of metabolism in the toxicity of a compound, therefore, enzyme induction may increase, decrease, or cause no change in the toxicity of a particular compound. The effects of induction need to be considered in the light of distribution and excretion as competing processes (chap. 4, Fig. 72 and chap. 6, Fig. 1). However, the consequences can be simply summarized and explained as follows ... 

Diet. The constituents and amount of food (deficiency/starvation) may influence disposition and hence toxicity of chemicals. Food constituents may be enzyme inducers or inhibitors. Lack of food or specific constituents (e.g., protein or vitamins) may decrease metabolic capability, for example, a protein-deficient diet decreases cytochrome P-450 activity. Lack of sulfur amino acids decreases glutathione level. The effect on toxicity will depend on the role of metabolism. 

Enzyme inhibition. The enzymes of biotransformation may be inhibited by a single exposure to chemicals. This occurs by several mechanisms formation of a complex, competition between substrates, destruction of the enzyme, reduced synthesis of the enzyme, allosteric effects, and lack of cofactors. The consequences will depend on the role of metabolism in toxicity in the same way as induction (see above). 

Hexachlorobutadiene is toxic to which organ. Briefly explain the role of metabolism in the mechanism. 

Timbrell JA. The role of metabolism in the hepatoxicity of isoniazid and iproniazid. Drug Metab Rev 1979 10 125. 

One of the major obstacles to definitively examining the role of formulation components on enterocyte-based processes is the possible effect of excipient inclusion on other complicating factors. For example, the inclusion of lipids or surfactants in in vitro metabolic or transport screens runs the risk of affecting the thermodynamic activity of the drug in solution, thereby obscuring the role of metabolic and transport processes. Similarly, some surfactants and lipid-surfactant conjugates may cause transient increases in intestinal permeability as... 

Wright, A.S. The role of metabolism in chemical mutagenesis and chemical carcinogenesis. ICPEMC Working Paper 2/2. Mutat. Res. 75 215-241, 1980. 

Symposium, The Role of Metabolic Activation in Producing Mutagenic and Carcinogenic Environmental Chemicals, February 9-11 Research Triangle Park, N.C. 

Behr T, Becker W, Hannappel E, Goldenberg DM, Wolf F.Targeting of liver metas-tases of colorectal cancer with IgG,F(ab )2, and Fab anti-carcinoembryonic antigen antibodies labeled with 99mTc the role of metabolism and kinetics. Cancer Res 1995 55 5777s-85s. 

Because there are many ways to achieve a given level of bioavailability, it makes sense to consider using a compartmental model to predict bioavailability rather than simply training a model on a set of bioavailability results. The role of metabolism tends to dominate most often and variability in drug response is greatly influenced by this. Drugs that are efficiently eliminated by the liver often have high variability in the plasma levels both within and between individuals... 

Studies of the role of metabolic transporters in the control and modulation of metabolic fluxes have provided somewhat ambiguous results in the case of respiration and gluconeogenesis. The role of the glutamate transporter in the acute control of ammonia formation seems clear at this time, and a proposed role of the malate/a-ketoglutarate carrier in chronic acidosis is an intriguing possibility. 

The role of metabolism and/or metabolic products of membrane phospholipids under the influence of PLC and PLA2 has been reviewed by Henquin (1985) and Morgan and Montague (1992). 

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