Intracellular targets

Two mechanisms are operating alone or in concert to minimize the antibiotic concentration at the intracellular target site Downregulation of the expression of the pore proteins, also called porins, and upregulation of one or a set of several unspecific efflux pumps. However, the impact of these mechanisms on the resistance is low, since due to the essential function of porins for uptake of nutrients their reduction is limited and to avoid disturbances of membrane integrity due to extensive oveiproduction of mdr efflux pumps these are subjected a strict regulation. 

Antidepressant Drugs. Figure 1 Effects of stress as a model for depression and the reversal by the use of antidepressants. Multiple intracellular targets might be involved in the regulation of plasticity and resilience by antidepressants, which block extracellular transporters. Adapted from [1],... 

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

An important observation linking Ca + to hormone action involved the definition of the intracellular targets of Ca action. The discovery of a Ca -dependent regulator of phosphodiesterase activity provided the basis for a broad understanding of how Ca and cAMP interact within cells. 

Fig. 9.1 Schematic representation of possible mechanisms of resistance in Gram-negative and Gram-positive bacteria. 1, antibiotic-inactivating enzymes 2, antibiotic efflux proteins 3, alteration or duplication of intracellular targets 4, alteration of the cell membrane reducing antibiotic uptake 5, alterations in porins or lipopolysaccharide reducing antibiotic uptake or binding.

Hyslop, P.A., Hinshaw, D.B., Halsey, W.A., Schraufttatter, I.U., Sauerheber, RD., Spragg, RG., Jackson, J.H. and Cochrane, C.G. (1988). Mechanisms of oxidant-mediated cell injury. The glycolytic and mitochondrial pathways of ADP phosphorylation as major intracellular targets inactivated by hydrogen peroxide. J. Biol. Chem. 263, 1665-1671. 

In the case of plasmid DNA the intracellular target (i.e., transcription machinery) is located in the nucleus. Plasmid DNA is a much larger molecule than oligonucleotides, and... 

Many non-receptor tyrosine kinases have been identified as products of retrovirally encoded oncogenes. Non-receptor tyrosine kinases can be divided into two groups transmembrane and cytosolic families. The c-src tyrosine kinase is the prototype of the cytosolic tyrosine kinases. Regions within these non-receptor tyrosine kinases share homology with the Src kinase, known as Src homology 2 and 3 (SH2 and SH3) domains, and mediate protein-protein interactions between the receptor tyrosine kinases and the intracellular targets (reviewed in Cantley et al., 1991 Pawson and Gish, 1992 Mayer and Baltimore, 1993). 

In these situations, biological activity will be reduced for reactive substrates that are consumed intracellularly or in a biological assay. In the case of TV-acyloxy-TV-alkoxyamides, those mutagens that are less prone to solvolysis or reaction with adventitious nucleophiles such as glutathione, will be present at higher concentrations at DNA, the intracellular target. 

Intracellular targets can present a more complex situation with respect to the application of the free drug principle. The unavailability of reliable general methods for determining free drug concentrations inside the cell (as opposed to total drug associated with the cell, which can usually be measured), often renders... 

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