salicylates and 4-nitrobenzoic-acid

Octanoate, salicylate, valproic acid, p-octyl-, p-nitro-, and p-chlorobenzoic acids were effective inhibitors of benzoic acid activation to benzoyl-CoA by mitochondrial extracts. p-Aminobenzoic acid was much less effective. Of these compounds, only salicylate and p-nitrobenzoic acid were not activated to their respective CoA esters. Salicylate, p-chloro- and p-nitrobenzoic acids effectively prevented inhibition of glucose synthesis and alpha-keto[1-14C]isovalerate oxidation by valproic acid, p-octyl-, and p-aminobenzoic acids, p-Octyl- and p-aminobenzoic acids greatly depleted hepatocyte free CoA and acetyl-CoA contents and increased the content of acid-insoluble and acid-soluble CoA esters respectively. p-Chloro- and p-nitrobenzoic acids prevented the sequestration of CoA as p-octylbenzoyl-CoA or p-aminobenzoyl-CoA in hepatocytes incubated with these compounds. p-Chlorobenzoic acid not only prevented but also reversed the inhibition of gluconeogenesis in hepatocytes incubated with p-octylbenzoic acid. These results suggest that p-chloro- or p-nitrobenzoic acids might be effectively used to reverse some of the hepatotoxic effects of the CoA esters of valproic acid or naturally-occurring organic acids, such as those which accumulate in Reye's Syndrome or organic acidemias.

Topics: 4-Aminobenzoic Acid; Ammonia; Animals; Benzoates; Benzoic Acid; Coenzyme A; Fatty Acids; Glucose; In Vitro Techniques; Liver; Male; Nitrobenzoates; Rats; Salicylates; Salicylic Acid; Valproic Acid

p-Aminobenzoic acid (PABA) exerts three metabolic effects on E. coli: it acts as a normal vitamin at low concentrations, as a source of another vitamin, p-hydroxybenzoic acid (POB), at moderate concentrations, and as a growth inhibitor at high concentrations (150 to 1600 microg./ml.). The inhibition is competitively reversed by POB in 1/100 the concentration of PABA. The inhibition is also reversed to a limited extent by shikimic acid and compound X, precursors of POB. p-Nitrobenzoic acid is an inhibitory competitor of both POB and PABA. The retardation of growth produced by PABA and other competitive analogues of POB (p-nitrobenzoic acid; 4,4'-dihydroxydiphenyl sulfone; phenosulfazole) is converted to complete bacteriostasis by the addition of L-aspartic acid in a remarkably low concentration (1 microg./ml.)) without change in the competitive ratio with POB. The mechanism underlying this synergism is not clear. In contrast to wild type, mutants that require POB not only are inhibited by much lower concentrations of the above analogues, but also show inhibition by weaker competitors of POB such as p-hydroxybenzenesulfonamide, p-chlorobenzoic acid, and p-fluorobenzoic acid.

Topics: 4-Aminobenzoic Acid; Escherichia coli; Hydroxybenzoates; Nitrobenzoates; Salicylates