Inhibition of metabolic processes by coenzyme-A-sequestering aromatic acids. Prevention by para-chloro- and para-nitrobenzoic acids.
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.
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000641:Ammonia / Q000097:blood; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D019817:Benzoic Acid; D003065:Coenzyme A / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000096:biosynthesis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D009579:Nitrobenzoates / Q000494:pharmacology; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D020156:Salicylic Acid; D014635:Valproic Acid / Q000494:pharmacology*
D001565:Benzoates; D005227:Fatty Acids; D009579:Nitrobenzoates; D012459:Salicylates; D014635:Valproic Acid; D000641:Ammonia; D019817:Benzoic Acid; C008629:4-nitrobenzoic acid; D005947:Glucose; D020156:Salicylic Acid; D003065:Coenzyme A; D010129:4-Aminobenzoic Acid