Inducers enzyme synthesis affected

The majority of antiviral drugs which are under clinical development today generally interrupt viral nucleic acid synthesis. These compounds often do not affect host cell metabolism and possess considerable selectivity against virus-induced enzymes. This article discusses agents exhibiting significant antiviral activity against viral infections in animal model systems. 

Much like the phenolic acids, early work with scopoletin showed it inhibited oxidation of IAA and thus could affect growth in this manner. Inhibition of several other enzymes by scopoletin and coumarin has been shown. Coumarin was reported to induce ethylene synthesis.47 Also, it is one of several phenolic compounds that antagonize abscisic acid-induced inhibition of growth and stomatal closure.52 Undoubtedly, these and possibly other interactions with hormones are part of the physiological action of the coumarins. 

The response of the liver to any form of biliary tree obstruction induces the synthesis of ALP by hepatocytes. Some of the newly formed enzyme enters the circulation to increase the enzyme activity in serum. The elevation tends to be more notable (greater than threefold) in extrahepatic obstruction (e.g., by stone or by cancer of the head of the pancreas) than in intrahepatic obstruction and is greater the more complete the obstruction. Serum enzyme activities may reach 10 to 12 times the upper reference limit and usually return to normal on surgical removal of the obstruction. A similar increase is seen in patients with advanced primary liver cancer or widespread secondary hepatic metas-tases. Liver diseases that principally affect parenchymal cells, such as infectious hepatitis, typically show only moderately (less than threefold) increased or even normal serum ALP activities (Table 21-3). Increases may also be seen as a consequence of a reaction to drug therapy. Intestinal ALP... 

Use of a high field to activate a membrane enzyme was first reported by Witt et al. (25) in 1976. They used dc pulses of approximately 1 kV/cm and of 1-ms duration to induce ATP synthesis by the chloroplast ATPase. Following this initial work, there have been many reports on 1-kV/ cm dc field-induced ATP synthesis in different ATP synthetic systems (see the literature cited in references 13 and 14). The main conclusion from these studies is that an applied field-induced transmembrane potential can facilitate ATP release from the enzyme whether a PEF can affect enzyme turnover is not clear. Because 1-kV/ cm dc fields also cause severe Joule heating of a sample suspension, thermal effects cannot be easily avoided except when very short electric pulses (microseconds) are used. Thus, the method has limited utility for electroactivation experiments. The PEF method is, however, quite popular for the study of electroporation and electrofusion of cell membranes (see the chapter by J. Weaver in this volume), electroinsertion of membrane proteins (26), and electrotransfection of cells (27). 

Post-Translational Inhibition of COX by Vitamin E. Because changes in COX activity reflect changes in the rate of enzyme synthesis or the rate of mRNA transcription, we further examined COX protein and mRNA expression. As determined in our previous study (9), LPS-induced COX-2 mRNA and COX-2 protein expression were not affected by vitamin E supplementation (9). Thus, we suggested that the vitamin E-induced decrease in COX activity of M< ) from old mice is not due to its regulation of COX transcription or translation rather, it appears that vitamin E exerts its effect post-translationaUy. 

In vivo, DNA synthesis seems more sensitive to intercalating agents than RNA synthesis, and the observed profound disturbance of DNA metabolism can account for the action of these drugs on cell growth and division. RNA, and consequently protein formation, are also affected. The appearance of inducible enzymes is prevented by profiavine or ethidium bromide, proving that there is a block in the synthesis of new messenger RNA. 

In animal studies, high levels of cortisol have been shown to induce (increase) the activity of the enzyme tryptophan 2,3-dioxygenase in the liver, thereby decreasing the bioavailability of tryptophan to the brain. It is interesting to note that low acute doses of a number of different antidepressants inhibit the activity of this enzyme and, as a result, increase brain tryptophan concentrations, thus stimulating 5-HT synthesis (Badawy and Evans, 1982). In this way a link between the two key monoamine neurotransmitters and the hormone may be seen namely, reduced brain NA activity leads to decreased inhibition of the HPA axis, while increased levels of cortisol reduce 5-HT activity in the brain. Activation of the HPA axis has also been shown to result in tissue atrophy, in particular of the limbic system s hippocampus, and a reduction in the levels of neurotrophic factors responsible for the maintenance and optimal function of brain neurons (Manji et al., 2001). In conclusion, manipulation of the HPA axis (Nemeroff, 2002) and stimulation of neurotrophic factor activity (Manji et al., 2001) might open up new avenues for the treatment of affective disorders. 

The affect of Li+ on the metabolism of serotonin (5-hydroxytryp-tamine, 5-HT) is equivocal. A number of studies consistently find a Li+-induced increase in the levels of the major metabolite, 5-hydroxyin-doleacetic acid (5-HIAA), in rat brain and in human CSF [155], which appears to reflect an increase in the rate of synthesis of 5-HT [156]. Li+-induced increases in the level of the amino acid precursor, tryptophan, and in the uptake of tryptophan by brain have also been reported [157], implying elevated tryptophan availability during Li+ treatment. In rat brain, chronic Li+ decreases the activity of tryptophan hydroxylase, the enzyme which, when activated by a Ca2+ and calmodulin-dependent protein kinase, leads to the synthesis of 5-HT [158]. Ca2+ increases the strength of binding of tryptophan to the enzyme, whereas Li+ has the opposite effect [159]. Tryptophan uptake is coupled to 5-HT utilization by a negative feedback mechanism and, therefore, the Li+-induced inhibition of tryptophan hydroxylase with a resultant decrease in 5-HT utilization could produce the observed increase in tryptophan uptake. 

The Li+-induced inhibition of the production of the HSV virus may be related to its actions upon viral DNA polymerase production and activity. Li+ reduces both the synthesis of DNA polymerase in tissue culture and the activity of DNA polymerase in vitro, each by about 50%. It has been proposed that Li+ reduces the biosynthesis of viral polypeptides and nucleic acids, and hence inhibits viral DNA replication by competition with Mg2+, a cofactor of many enzymes [243]. However, the inhibitory effect of Li+ on HSV replication in tissue culture is not affected by Mg2+ levels. A more likely hypothesis is the alteration of the intracellular K+ levels, possibly modifying levels of the high-energy phosphate compounds by replacement of either Na+ or K+ in Na+/K+-ATPase [244]. In tissue culture, HSV replication has been shown to be affected by the... 

The protein p21 can be induced by p53-independent factors, including drugs known as statins. These drugs are used to lower blood cholesterol by inhibition of its synthesis, via the enzyme HMG-CoA reductase. It is not known how statins affect the p21 protein. 

Carbamoyl phosphate synthetase formation in liver taken from tadpoles treated with thyroxine is enhanced by the addition of orotic acid, uracil or uridine (cytosine and adenosine had no effect). The synthesis of this enzyme is not affected by these pyrimidines in untreated animals. This indicates that there is a relative pyrimidine deficiency during thyroxine-induced metamorphosis [140]. 

Phenolic compounds naturally occurring in plants have induced many physiological responses that duplicate those reported for ozone and/or peroxyacetylnitrate (PAN). Chlorogenic acid is a competitive inhibitor of lAA-oxidase (35) and plant growth is adversely affected by increased concentrations of auxins (36). Concentrations of chlorogenic acid are increased in tobacco tissue exposed to ozone ( ) Phenols inhibit ATP synthesis (37), oxidative phosphorylation ( ) and SH enzyme activity (27) they increase respiration (38), reduce CO2 fixation (22), modify both membrane permeability (40) and oxidation rate of reduced NADH... 

Heavy metals stimulate or inhibit a wide variety of enzyme systems (16, 71, 72), sometimes for protracted periods (71, 73). These effects may be so sensitive as to precede overt toxicity as in the case of lead-induced inhibition of 8 ALA dehydrase activity with consequential interference of heme and porphyrin synthesis (15, 16). Urinary excretion of 8 ALA is also a sensitive indicator of lead absorption (74). Another erythrocytic enzyme, glucose-6-phosphatase, when present in abnormally low amounts, may increase susceptibility to lead intoxication (75), and for this reason, screens to detect such affected persons in lead-related injuries have been suggested (76). Biochemical bases for trace element toxicity have been described for the heavy metals (16), selenium (77), fluoride (78), and cobalt (79). Heavy metal metabolic injury, in addition to producing primary toxicity, can adversely alter drug detoxification mechanisms (80, 81), with possible secondary consequences for that portion of the population on medication. 

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