Microsomes protein synthesis

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for... 

Bennett WM, Mela-Riker LM, Houghton DC, Gilbert DN, Buss WC, Microsomal protein synthesis inhibition an early manifestation of gentamicin nephrotoxicity. Am J Physiol, 1988 24 F265-69. 

B. Selective Interference with Mitochondrial and Microsomal Protein Synthesis... 

The use of inhibitors has helped characterize the mitochondrial protein synthesis reaction in two ways. On the one hand, information on the mechanism may be gained with some inhibitors. And on the other hand, some inhibitors (especially antibiotics) are useful in distinguishing mitochondrial protein synthesis from that in the microsomal fraction. These inhibitors may be divided into three different groups (1) Those which interfere with both mitochondrial and microsomal protein synthesis (2) compounds which selectively inhibit microsomal protein synthesis and (3) inhibitors which interfere only with mitochondrial protein synthesis. 

The question remains whether CAP under certain circumstances blocks protein synthesis at the 80 S ribosome. In a cell-free system of reticulocyte microsomes (Weisberger et al., 1964 Beard et oL, 1969) an inhibition of the association of mRNA and the 40 S ribosomal subunit was reported. In the reticulocyte system used 70-100% inhibition of [ Cjleucine incorporation was reported at 0.1 pmole/ml of CAP with either endogenous template RNA or small amounts of poly(U). These results could not be confirmed by Zelkowitz et al. (1968). We also found no striking inhibition of poly (U)-directed amino acid incorporation by CAP in messenger-depleted cell-free systems from rat liver or rat embryos (Uehlin et al, 1974). From all this it seems clear that generally CAP has no striking effect on protein synthesis at the 80 S ribosome level. But inhibition of mammalian microsomal protein synthesis under certain conditions cannot be ruled out. 

Further work is needed to establish if ferrochelatase is under control of the mitochondrial genome. This is especially interesting since it may indicate control of the microsomal protein synthesis of heme proteins by the heme formed under mitochondrial regulation. Control of microsomal protein synthesis by heme has been shown in several laboratories (Tavill et al, 1972 Balkow et al, 1973 Mathews et al, 1973). 

In contrast to the hepatotoxic action of coumarin, 4-methylcoumarin triggered off a protective mechanism by increasing microsomal protein synthesis. The... 

Recently, it has been reported that coumarin and some closely related derivatives administered in vivo stimulated the incorporation of labelled amino acids in the liver [223, 224] the endogenous and poly U-directed microsomal protein synthesis were also increased [225]. The relation of this increased de novo protein synthesis to the induction of drug metabolising enzymes is not clear as coumarin was found to inhibit drug metabolism [66]. However, coumarin brought about a decreased incorporation of amino acids by liver slices in vitro [226]. 

Schreiber, S. S., Oratz, M., Rothschild, M. A., Reef, F. and Evans, C. (1974) Alcoholic cardiomyopathy. II. The inhibition of cardiac microsomal protein synthesis by acetaldehyde. J. Molec. Cell. Cardiol. 6, 207. 

The relative importance of hepatic microsomal lipid peroxidation versus covalent binding of carbon tetrachloride-derived radicals has been the subject of considerable debate. Since cytochrome P-450 loss has been shown to be related to lipid peroxidation and to covalent binding, each in the absence of the other, both of these early consequences of carbon tetrachloride metabolism may contribute to P-450 destruction. Nevertheless, it is still not clear how these initial events are related to subsequent triglyceride accumulation, polyribosomal disaggregation, depression of protein synthesis, cell membrane breakdown and eventual death of the hepatocytes. Carbon tetrachloride... 

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides. 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

These observations are consistent with the conclusion that auxin treatment leads to the synthesis of BS cellulase, which then accumulates in smooth ER vesicles. There is direct evidence that the synthesis occurs in rough ER vesicles (11). Cellulase activity was shown (25) to increase in RNA-rich pea microsomes, provided these were isolated from auxin-treated tissue, when the preparations were incubated with ingredients necessary for carrying out protein synthesis in vitro. Messenger RNA (mRNA) from these microsomes has been translated in a different ribo-somal system and shown to synthesize BS cellulase protein (II). Thus, it is legitimate to use the term "induction to apply to the ability of auxin to evoke the appearance of mRNA for BS cellulase. 

Mechanism and Genetics of Induction in Mammals. Many different mechanisms may be involved in CYP induction. These include increased transcription of DNA, increased mRNA translation to protein, mRNA stabilization, and protein stabilization. Induction can only occur in intact cells and cannot be achieved by the addition of inducers directly to cell fractions such as microsomes. It has been known for some time that in most cases of increase in monooxygenase activity there is a true induction involving synthesis of new enzyme, and not the activation of enzyme already synthesized, since induction is generally prevented by inhibitors of protein synthesis. For example, the protein synthesis inhibitors such as puromycin, ethionine, and cyclo-heximide inhibit aryl hydrocarbon hydroxylase activity. A simplified scheme for gene expression and protein synthesis is shown in Figure 9.7. 

The aminoacyl transfer reaction, one of the latter stages in protein synthesis, involves incorporation of amino acids from soluble ribonucleic acid-amino acid into ribosomal protein. This reaction requires guanosine triphosphate and a soluble portion of the cell. Evidence has been obtained with rat liver preparations that aminoacyl transfer is catalyzed by two protein factors, aminoacyl transferases (or polymerases) I and n, which have been resolved and partially purified from the soluble fraction. Transferase n activity has also been obtained from deoxycholate-soluble extracts of microsomes. With purified transferases I and n, incorporation is observed with relatively low levels of GTP its sulfhy-dryl requirement is met by a variety of compounds. The characteristics of this purified amino acid incorporating system, in terms of dependency on the concentration of its components, are described. 

Pharmacokinetics Both T4 and T3 are absorbed after oral administration. T4 is converted to T3 by one of two distinct deio-dinases, depending on the tissue. T3 combines with a receptor to stimulate subsequent protein synthesis necessary for normal metabolism. The hormones are metabolized through the microsomal P-450 system. Drugs such as phenytoin, rifampin, phe-nobarbital, etc. that induce the P-450 enzymes accelerate metabolism of the thyroid hormones. 

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