Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine.
Glycine conjugation of benzoic acid is catalyzed by the mitochondrial enzymes benzoyl-coenzyme A(CoA) synthetase and benzoyl-CoA: glycine N-acyltransferase and requires ATP, CoA, and glycine as cosubstrates. Lipoic acid (LA), an important endogenous and also therapeutic compound, depletes hepatic CoA; therefore, it may interfere with glycine conjugation. To test this hypothesis, LA (0.5-1.5 mmol/kg ip) was given to anesthetized, glycine-loaded rats 1 hr before administration of benzoic acid (1 mmol/kg iv). LA inhibited glycine conjugation of benzoic acid in a dose-dependent manner as indicated by: 1) reduced clearance of benzoic acid from blood; 2) delayed appearance of benzoylglycine in blood; and 3) decreased excretion of benzoylglycine in urine. LA also decreased urinary excretion of injected benzoylglycine, indicating that reduced excretion of this metabolite after benzoic acid injection is caused by diminished formation and impaired renal transport of benzoylglycine. Urine formation was decreased by LA in a dose-dependent fashion, and acute renal failure was evident in rats receiving the highest dose. LA depleted hepatic CoA, carnitine, and glutathione, but not ATP, whereas it increased the hepatic concentration of glycine. In isolated and solubilized rat liver mitochondria, LA inhibited both benzoyl-CoA synthetase (IC50 approximately 1.5 mM) and benzoyl-CoA:glycine N-acyltransferase (IC50 approximately 0.3 mM). Thus, depletion of CoA and inhibition of the pertinent enzymes seem responsible for impairment of glycine conjugation of benzoic acid by LA. LA may also impair renal tubular cell function, compromising the tubular secretion of benzoylglycine and causing acute renal failure.
Gregus
Z
Z
Department of Pharmacology, University Medical School of Pécs, Hungary.
Fekete
T
T
Halászi
E
E
Klaassen
C D
CD
D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D019817:Benzoic Acid; D003066:Coenzyme A Ligases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000378:metabolism*; D006626:Hippurates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*
D001565:Benzoates; D006626:Hippurates; D008063:Thioctic Acid; D019817:Benzoic Acid; D000217:Acyltransferases; C002807:benzoyl-CoA-glycine N-acyltransferase; D003066:Coenzyme A Ligases; C055455:benzoate coenzyme A ligase; C030514:hippuric acid; D005998:Glycine