Tetracyclines 13-oxidation inhibition

Fatty acid beta-oxidation Inhibition by valproate, tetracyclines, nonsteroidal antiinflammatory drugs, antianginal cationic amphiphilic drugs, female sex hormones, CoA depleters such as valproate and salicylate... 

In experimental animals, tetracycline and the various tetracycline derivatives lead to extensive microvesicular steatosis of the liver (Freneaux et al. 1988 Labbe et al. 1991). This marked steatogenic effect is due to the dual effects of the tetracyclines, which inhibit both the mitochondrial B-oxidation of fatty acids (Freneaux et al. 1988 Labbe et al. 1991) and also MTP activity, thus decreasing the hepatic secretion of very low-density lipoproteins (Letteron et al. 2003). 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

Iron absorption occurs predominantly in the duodenum and upper jejunum. The physical state of iron entering the duodenum greatly influences its absorption. At physiological pH, ferrous iron is rapidly oxidized to the insoluble ferric form. Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. When gastric acid production is impaired, iron absorption is reduced substantially. Ascorbic acid enhances iron absorption. Ascorbic acid mobilizes iron from iron-binding proteins in vivo, which in turn could catalyze lipid peroxidation. Iron absorption is inhibited by antacids, phytates, phosphates and tetracyclines. 

There are several drugs that inhibit beta oxidation of fatty acids in mitochondria leading to lipid accumulation, such as aspirin, valproic acid, and tetracyclines. 

Two further perspectives on the use of tetracychnes in rheumatoid arthritis have been pubhshed (14,15). In addition to an effect on matrix metalloproteinases, the authors focused on a potential antiarthritic action of tetracyclines by their effects in the interaction between the generation of nitric oxide, matrix metalloproteinase release, and chondrocyte apoptosis. Both minocychne and doxycycline inhibit the production of nitric oxide from human cartilage and murine macrophages (16) in concentrations that are achieved in vivo. The authors suggested that tetracyclines may have several potential chondroprotective effects direct inhibition of matrix metalloproteinase activity and, by inhibition of nitric oxide production, further reduction of matrix metalloproteinase activity, reversal of reduced matrix synthesis, and reduced chondrocyte apoptosis. 

Early explanations of the mechanism of action of tetracyclines involved their demonstrated ability to inhibit various bacterial enzymes that catalyzed such biochemically essential reactions as glucose oxidation and oxidative phosphorylations. Their ability effectively to chelate di- and trivalent metallic ions was also invoked in the theorization. However, at clinically achievable serum levels the bacteriostatic effects of tetracyclines are now accepted to involve primarily direct inhibition of protein synthesis. 

Freneaux E, Labbe G, Letteron P, Le Dinh T, Degott C, Geneve J, Larrey D, Pessayre D (1988) Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man possible role in microvesicular steatosis induced by this antibiotic. Hepatology 8 1056-1062... 

The tetracyclines inhibit the synthesis of bacterial protein in low concentrations, but their action is less specific than that of chloramphenicol. In higher concentrations they also inhibit oxidative processes and the synthesis of nucleic acids and cell walls. Some of these secondary effects may be attributed to the fact that the tetracyclines are chelating agents for metal ions. 

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