Cellular mediated reaction

Currently allergic reactions are classified into four types on the basis of different reaction patterns. Whereas types I—III are dependent on antibodies, the type IV reaction is mediated by cellular immune reactions. 

Delayed type hypersensitivty (DTH) reactions (synonym type IV allergic reactions) are exaggerated, T-lymphocyte mediated, cellular immune reactions to foreign substances, which require one to two days to manifest clinical symptoms. 

As already discussed in chapter 4, reactive intermediates can react with reduced GSH either by a direct chemical reaction or by a GSH transferase-mediated reaction. If excessive, these reactions can deplete the cellular GSH. Also, reactive metabolites can oxidize GSH and other thiol groups such as those in proteins and thereby cause a change in thiol status. When the rate of oxidation of GSH exceeds the capacity of GSH reductase, then oxidized glutathione (GSSG) is actively transported out of the cell and thereby lost. Thus, reduced GSH may be removed reversibly by oxidation or formation of mixed disulfides with proteins and irreversibly by conjugation or loss of the oxidized form from the cell. Thus, after exposure of cells to quinones such as menadione, which cause oxidative stress, GSH conjugates, mixed disulfides, and GSSG are formed, all of which will reduce the cellular GSH level. 

Many chemicals form reactive, electrophilic intermediates and free radicals during their metabolism in the body. These can be formed via enzyme-mediated reactions (many of which are oxidations) or from autoxidation of small molecules like flavins and thiols. These electrophilic intermediates covalently react with nucleophilic sites in the cell, including glutathione (GSH) and thiol-containing proteins, causing cellular... 

The general principle involving cellular CO2 reactions is mediated by carbonic anhydrase in the sensors CA... 

The final mechanism for an immune-mediated reaction is the production of autoantibodies to a spoiled membrane. The offending drug alters the neutrophil membrane, which induces the formation of autoantibodies (antibodies that attach directly to the neutrophil). Their attachment to the neutrophil causes cellular destruction by the phagocytic system. 

Two major types of mechanisms have been proposed to account for DILL The first mechanism involves the intrinsic hepatotoxicity of a particular drug itself or, more frequently, a result of the toxic effects of its metabolites on vital cellular targets of the liver. The second mechanism reflects an immune-mediated reaction culminating in hepatic inflammation and injury. 

Although the COX reaction requires catalytic levels of peroxide, the enzyme activity is not directly affected by ROS production (Smith 2008). However, ROS-mediated increase of the inducible enzymes involved in the arachidonic acid cascade, including phospholipases that provide free AA and other PUFA substrates for COX-mediated reactions, COX-2 and prostaglandin synthases (see Section 3.1), makes the formation of eicosanoids sensitive to the cellular redox status, and this can impact on disease states characterized by oxidative stress (Korbecki et al. 2013). 

Also of interest, P5C reductase from various tissue or cellular sources are differentially sensitive to inhibition by proline (99,117), NADP (86, 117), and adenine nucleotides (86). The enzyme from cultured fibroblasts is sensitive to inhibition by proline and its inhibition of the NADH-mediated reaction (K, = 2 X 10 M) is much greater than of the NADPH-mediated reaction (K = 2 X 10 M). By contrast, the hepatic and erythrocyte enzymes are insensitive to proline but very sensitive to inhibition by NADP+ (H7). Adenine nucleotides also inhibit the hepatic enzyme (86) but not the erythrocyte enzyme. These differential patterns of inhibition suggest that there are isozymes of P5C reductase found in various tissues, an interpretation further supported by the relative deficiency of the NADH-mediated activity in a leukemia cell line (55). Whether these putative isozymes are products of different genes or are interconvertible forms is an intriguing question which awaits definitive studies on enzyme prepared from different sources. 

The sensitivity of cellular constituents to environmental extremes places another constraint on the reactions of metabolism. The rate at which cellular reactions proceed is a very important factor in maintenance of the living state. However, the common ways chemists accelerate reactions are not available to cells the temperature cannot be raised, acid or base cannot be added, the pressure cannot be elevated, and concentrations cannot be dramatically increased. Instead, biomolecular catalysts mediate cellular reactions. These catalysts, called enzymes, accelerate the reaction rates many orders of magnitude and, by selecting the substances undergoing reaction, determine the specific reaction taking place. Virtually every metabolic reaction is served by an enzyme whose sole biological purpose is to catalyze its specific reaction (Figure 1.19). 

PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-RTKs. The human genome encodes for a total of 90 tyrosine kinases of which 32 are nonreceptor PTKs that can be placed in 10 subfamilies (Fig. 1). All nonreceptor PTKs share a common kinase domain and usually contain several additional domains that mediate interactions with protein-binding partners, membrane lipids, or DNA (Table 1). These interactions may affect cellular localization and the activation status of the kinase or attract substrate proteins for phosphorylation reactions. 

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