Physiological processed mediated

Table 13,1 Examples of physiological processes mediated by G proteins...

Oral availability is a complex parameter that involves several chemical and physiological processes such as solubility, chemical stability, permeability and first-pass metabolism, to mention a few. All of these subprocesses depend on two different types of factor (i) interaction of the drug compound with certain macromolecules, such as the metabolism mediated by the cytochromes P450 family and (ii) interaction of the drug molecule with a certain chemical or biological environment, that will determine the solubility or the passive permeability. 

Ubiquitin-proteasome-mediated proteolysis plays a critical role in many physiological processes including cell cycle and development. In the nervous system, proteolysis plays a role in the formation of synaptic connections during development as well as in alteration of synaptic strength (synaptic plasticity) that occurs during learning and memory. The role of proteolysis in cell cycle and synaptic plasticity will be considered in detail below. 

Cell cycle is one of the physiological processes in which the role of uhiquitin—proteasome-mediated proteolysis is well established. With the advent of yeast mutants that interfered with various phases of the cell cycle, cyclin-dependent kinases (Cdks) were found to have a critical role in regulating the cell cycle. Typically, Cdks activated hy regulatory proteins are known as cyclins. Different Cdk—cyclin complexes are formed at specific stages of the cell cycle such as the S-phase (in which DNA synthesis occurs) and the metaphase. The transition from metaphase to anaphase depends on degradation of cyclins. " " Systematic biochemical studies showed that cyclins were substrates for the uhiquitin—proteasome pathway (Table 5). 

The eicosanoids are a group of signaling substances that arise from the C-20 fatty acid arachidonic add and therefore usually contain 20 C atoms (Greek eicosa = 20). As mediators, they influence a large number of physiological processes (see below). Eicosanoid metabolism is therefore an important drug target. As short-lived substances, eicosanoids only act in the vicinity of their site of synthesis (paracrine effect see p.372). 

The role of the steroid hormone receptors has extensively been defined with the help of natural and synthetic agonists and antagonists and with characterisation of transgenic and knock-out mice. In experimental studies, both approaches have been useful tools for validating that a physiological process is indeed mediated by the steroid hormone receptor imder investigation. 

Prostaglandin (PC). Components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. 

In recent years, nitric oxide (NO) has emerged as one of the most interesting mediators of normal and patho physiological processes. NO is a highly reactive free radical, a lipophilic gas with a very short half-life in the range of 5 - 30 s under bioassay conditions (Palmer et al., 1987). NO is rapidly converted to nitrogen dioxide (N02), which again rapidly forms the more stable metabolites nitrite (N02 ) and nitrate (N03). 

Gold sodium thiomalate provides a stimulus for liver, kidney and possibly other cells to change the body distribution of zinc and copper. Proteins such as metalloproteins, superoxide dismutase and metallothioneins19 help the cell carry out this task. These essential metals are important in the physiological processes relevant to rheumatoid arthritis, and thus it also appears possible that the gold complexes may mediate their antiarthritic activity through an effect on the metabolism of zinc and copper. 

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