Inhibition of metabolic processes by coenzyme-a-sequestering aromatic acids. Prevention by para-chloro- and para-nitrobenzoic acids

Melanie S. Swartzentruber, Robert A. Harris

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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 α-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.

Original languageEnglish (US)
Pages (from-to)3147-3153
Number of pages7
JournalBiochemical Pharmacology
Volume36
Issue number19
DOIs
StatePublished - Oct 1 1987

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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