Metabolic cellular system

There is no shortage of dynamic phenomena observed in cellular systems [272], Quite on the contrary, cellular metabolism is a highly dynamic system, and... 

As argued in the previous sections, cellular metabolism is a highly dynamic process, and a description entirely in terms of flux balance constraints is clearly not sufficient to understand and predict the functioning of metabolic processes [334, 335], Specifically, we seek to demonstrate that the dynamic properties of large-scale metabolic networks play a far more important role than currently anticipated. Understanding the dynamics of metabolic networks will prove critical to a further understanding of metabolic function and regulation and critical to our ability to manipulate cellular system in a desired way. 

A variety of mammalian cell culture systems can be used to detect mutations induced by chemical substances. The L5178Y mouse l)nnphoma line, measuring mutation at the TK locus, is preferred. TK is an important enz)une involved in DNA synthesis. Cells are exposed to the test substance at various concentrations, in the presence and absence of a metabolic activation system, for a suitable period of time, and then subcultured to assess cytotoxicity and to allow phenotypic expression prior to mutant selection. Cells deficient in TK because of a forward mutation are resistant to the cytotoxic effects of pyrimidine analogues (antimetabolites), such as trifluorothymidine (TFT). This is because the antimetabolites cannot be incorporated into cellular nucleotides and kill the cell through inhibition of cellular metabolism. After treatment, cells are grown in a medium containing TFT mutant cells can proliferate in the presence of TFT, whereas normal cells containing TK are killed. This allows the detection of an increase in mutant... 

Cyanide ion exerts an inhibitory action on certain metabolic enzyme systems, most notably cytochrome oxidase, the enzyme involved in the ultimate transfer of electrons to molecular oxygen. Because cytochrome oxidase is present in practically all cells that function under aerobic conditions, and because the cyanide ion diffuses easily to all parts of the body, cyanide quickly halts practically all cellular respiration. The venous blood of a patient dying of cyanide is bright red and resembles arterial blood because the tissues have not been able to utilize the oxygen brought to them. Cyanide intoxication produces lactic acidosis, the result of an increased rate of glycolysis and production of lactic acid. ... 

Carbon tetrachloride is metabolized by CYP2 enzymes several reactive metabolites have been postulated, including radicals and phosgene. In vitro, DNA binding of carbon tetrachloride is observed in several cellular systems no such binding in vivo has been reported. 

Metabolic flux analysis is one of the most powerful analytical and experimental tools used for physiological characterisation of cell metabolism. In its most basic form, the method is essentially based on the conservation principles used for macrochemical and biological systems applied to the internal environment of cellular systems. The fundamental equation of MFA considers the steady-state mass balances around all intracellular metabolic intermediates such that... 

Toxicokinetics describe Absorption, Distribution, Metabolism and Elimination (ADME) of a chemical in humans, experimental animals or cellular systems. Of specific importance for interpretation of animal studies and for extrapolation of hazards between species is the comparative information on the exposure and the dose that reaches the critical target. 

In addition, CS reacts with the disulfhydryl form of lipoic acid, a coenzyme in the pyravate decarboxylase system (Olajos and Salem, 2001). Alteration in dihydrolipoic acid biochemistry can lead to decreased acetyl CoA levels, resulting in cellular injury. Therefore, tissue injury seems to be related to inactivation of these metabolic enzyme systems. The damage is transient because the enzymes can be rapidly reactivated if exposure is terminated (Beswick, 1983). 

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

Because clearance at the whole-body level often is determined by metabolism at the cellular level, it is possible to use a variety of human-derived in vitro systems to determine rates of metabolism. These systems include pure human enzymes (such as cytochrome P450 enzymes) (13) and human liver subcellular fractions (S9 and microsomes) (14). However, with enzymes and subcellular fractions, some information is lost because the whole-cell integration of subcellular processes has been disrupted. The use of cultured human hepatocytes retains the whole-cell integration at the expense of greater experimental complexity (15). Each system provides a different window on the metabolic processes, is relatively easy to use, and can be obtained from commercial sources. Rates and pathways of metabolism may be compared with a series of discovery compounds to identify those with the greatest relative metabolic stability or with a benchmark compound of known human PK characteristics to provide a more absolute estimate of hepatic metabolic clearance. 

Each single step of drug transport, binding, and metabolism involves some form of partitioning between an aqueous compartment and a nonaqueous phase, which could be a membrane, serum protein, receptor, or enzyme. In the case of isolated receptors, the endpoint is clear-cut and the critical step is evident. But in more complex systems, such as cellular systems or whole animals, many localized steps could be involved in the random-walk process and the eventual interaction with a target. 

Thomas D. J., Styblo M., and Lin S. (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol. Appl. Pharmacol. 176, 127-144. 

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