salicylates and 3-hydroxybenzoic-acid

An overview is presented of a selected number of mono-aromatic derivatives and their short-term effects on hepatic fatty acid biosynthesis. The compounds discussed in this paper are ortho-hydroxybenzoate (salicylate), meta-hydroxybenzoate, para-hydroxybenzoate, benzoate, para-t-butylbenzoate, para-aminosalicylate, clofibrate, halofenate, alpha-cyano-4-hydroxycinnamate and benfluorex. All of these drugs inhibit fatty acid biosynthesis by isolated rat liver cells, albeit with different effectiveness. In contrast, the compounds have differential effects on fatty acid esterification and oxidation by isolated hepatocytes. An attempt is made to describe in molecular terms the underlying mechanisms of the acute inhibitory effects of the mono-aromatic derivatives on hepatic lipogenesis. It is proposed that all of the drugs exert an inhibitory action at the level of acetyl-CoA carboxylase, the enzyme generally considered to catalyse the rate-limiting step in hepatic fatty acid synthesis. This inhibitory effect may be either direct, i.e. by an alteration of the enzyme's structure as a result of interaction between drug and enzyme, or indirect, i.e. through a drug-induced change in the cellular levels of allosteric effectors of acetyl-CoA carboxylase.

Topics: Acetyl-CoA Carboxylase; Aminosalicylic Acid; Animals; Benzene Derivatives; Benzoates; Benzoic Acid; Carbohydrate Metabolism; Clofibrate; Coumaric Acids; Fatty Acids; Fenfluramine; Halofenate; Hydroxybenzoates; Lipids; Liver; Models, Biological; Oxidation-Reduction; Parabens; Rats; Salicylates; Salicylic Acid

Rhodococcus erythropolis strain S1 uses the gentisate pathway to metabolize salicylate and m-hydroxybenzoate and the protocatechuate pathway to degrade p-hydroxybenzoate. m-Hydroxybenzoate 6-hydroxylase was induced by growth on m-hydroxybenzoate or gentisate, and salicylate 5-hydroxylase only by growth on salicylate. p-Hydroxybenzoate 3-hydroxylase could be induced only by growth on p-hydroxybenzoate. m-Hydroxybenzoate or p-hydroxybenzoate could repress the induction of salicylate 5-hydroxylase. Maleylpyruvate isomerase in the gentisate pathway did not require reduced glutathione.

Topics: cis-trans-Isomerases; Gentisates; Glutathione; Hydroxybenzoates; Isomerases; Kinetics; Mixed Function Oxygenases; Oxygen Consumption; Parabens; Rhodococcus; Salicylates; Salicylic Acid

Eight actinomycetes of the genera Amycolatopsis and Streptomyces were tested for the degradation of aromatic compounds by growth in a liquid medium containing benzoate, monohydroxylated benzoates, or quinate as the principal carbon source. Benzoate was converted to catechol. The key intermediate in the degradation of salicylate was either catechol or gentisate, while m-hydroxybenzoate was metabolized via gentisate or protocatechuate. p-Hydroxybenzoate and quinate were converted to protocatechuate. Catechol, gentisate, and protocatechuate were cleaved by catechol 1,2-dioxygenase, gentisate 1,2-dioxygenase, and protocatechuate 3,4-dioxygenase, respectively. The requirement for glutathione in the gentisate pathway was dependent on the substrate and the particular strain. The conversion of p-hydroxybenzoate to protocatechuate by p-hydroxybenzoate hydroxylase was gratuitously induced by all substrates that were metabolized via protocatechuate as an intermediate, while protocatechuate 3,4-dioxygenase was gratuitously induced by benzoate and salicylate in two Amycolatopsis strains.

Topics: Actinomycetales; Benzoates; Benzoic Acid; Glutathione; Hydroxybenzoates; Parabens; Salicylates; Salicylic Acid; Streptomyces

Electron microscopic and spectrophotometric studies showed that salicylate causes gross swelling of mitochondria in isotonic salt solutions. In overall morphology the salicylate-treated mitochondria resembled those from patients with Reye's syndrome. Salicylate analogs such as m-hydroxybenzoate, p-hydroxybenzoate, and benzoate did not exert this effect. The mitochondria deformed by salicylate tended to return to their original condensed form on removal of the drug.

Topics: Animals; Benzoates; Benzoic Acid; Hydroxybenzoates; Microscopy, Electron; Mitochondria, Liver; Mitochondrial Swelling; Parabens; Rats; Reye Syndrome; Salicylates

Recent investigations have demonstrated that inhibition of the cyclooxygenase enzyme of the prostaglandin synthetase complex accounts for most of the pharmacological effects of salicylate. To determine whether inhibition of cyclooxygenase activity (COA) plays a role in stimulation of ventilation (VE) by salicylate, sodium salicylate and other more potent inhibitors of COA (i.e., indomethacin and ibuprofen) were infused into anesthetized dogs. These experimental intravascular infusions lasted 1 hr; VE and oxygen consumption (VO2) were continuously measured. In the initial series of experiments, all COA inhibitors were infused at a rate of 25 mumol/kg/min. It was noted that only salicylate elicited consistent increases in either VE or VO2. The possibility that high infusion rates of potent COA inhibitors may prevent stimulation of VE by some additional toxic effect was explored in a second series of experiments in which we infused the minimal amount of COA inhibitors necessary to completely inhibit cyclooxygenase in other experimental situations. In these experiments, it was noted that none of the COA inhibitors (i.e., salicylate, meclofenamate, indomethacin or ibuprofen) stimulated either VE or VO2. These observations suggest that salicylate stimulates VE by a mechanism other than inhibition of prostaglandin synthetase. Because salicylate-induced increases in VE and VO2 followed a similar time course, these results are consistent with our concept that stimulation of VE by salicylate is related to tissue hypermetabolism.

Topics: Animals; Cyclooxygenase Inhibitors; Dogs; Dose-Response Relationship, Drug; Hydroxybenzoates; Ibuprofen; Indomethacin; Infusions, Intra-Arterial; Respiration; Salicylates; Sodium Chloride; Sodium Salicylate