Effects of fibrates on the glycine conjugation of benzoic acid in rats

Z. Gregus, Tibor Fekete, Éva Halászi, Ágnes Gyurasics, Curtis D. Klaassen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

In the course of glycine conjugation, benzoic acid is successively converted into benzoyl-CoA and benzoylglycine by mitochondrial enzymes (i.e. benzoyl-CoA synthetase and benzoyl-CoA/glycine N-acyltransferase, respectively), utilizing ATP, CoA, and glycine. Large doses of benzoate deplete CoA from the liver, suggesting that the supply of CoA may limit the capacity for glycine conjugation. Because fibrates are known to increase hepatic CoA synthesis, we examined whether treatment with fenofibrate or bezafibrate enhanced the capacity of rats to conjugate benzoic acid with glycine. Dietary administration of fenofibrate or bezafibrate (2.5 mmol/kg of feed, for 10 days) increased hepatic CoA levels 8-10-fold, while not affecting hepatic ATP levels; only fenofibrate elevated, albeit moderately, the concentration of glycine in liver. Hepatic mitochondria isolated from fibrate-fed rats, compared with those from controls, exhibited unchanged benzoyl-CoA synthetase activity but higher benzoyl-CoA hydrolase and lower benzoyl-CoA/glycine N-acyltransferase activities. Feeding with either fibrate increased liver mass by 50-60%. Control and fibrate-fed rats were administered benzoate at different doses, one to produce a large demand for CoA (i.e. 2 mmol/kg, iv) and two others to produce smaller demands for CoA (i.e. 1 mmol/kg or 2 mmol/kg plus glycine, iv). Fenofibrate-fed rats, and to a lesser extent bezafibrate-fed animals, exhibited increased glycine conjugation capacity, as indicated by faster disappearance of benzoate from the blood and appearance of benzoylglycine in the blood and urine, compared with controls; however, fibrates were not more effective in rats receiving the benzoate dose that produced the greatest demand for CoA. In contrast, benzoylglycine formation from benzoate (0.1-1 mM) was not enhanced in liver slices from fibrate-fed rats; moreover, it was lower than control levels in slices from bezafibrate-fed animals. Bezafibrate, but not fenofibrate, given to rats in a single dose (0.5 mmol/kg, ip) decreased the elimination and glycine conjugation of benzoate, indicating that bezafibrate is a direct inhibitor of glycine conjugation. In summary, fibrates influence glycine conjugation in a complex manner. Some fibrate-induced alterations (i.e. increased benzoyl-CoA hydrolase and decreased glycine transferase activities and direct inhibition by bezafibrate) can potentially hinder conjugation of benzoate with glycine, thus precluding conclusions regarding whether increased CoA availability enhances glycine conjugation. Fibrate-induced hepatomegaly appears to significantly contribute to the increased glycine conjugation capacity of rats treated with fenofibrate or bezafibrate.

Original languageEnglish
Pages (from-to)1082-1088
Number of pages7
JournalDrug Metabolism and Disposition
Volume26
Issue number11
Publication statusPublished - Nov 1998

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Fibric Acids
Benzoic Acid
Glycine
Rats
Bezafibrate
Coenzyme A
Fenofibrate
Benzoates
Liver
Hydrolases
Animals
Blood
Adenosine Triphosphate
Mitochondria
Hepatomegaly
Level control
Transferases

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Gregus, Z., Fekete, T., Halászi, É., Gyurasics, Á., & Klaassen, C. D. (1998). Effects of fibrates on the glycine conjugation of benzoic acid in rats. Drug Metabolism and Disposition, 26(11), 1082-1088.

Effects of fibrates on the glycine conjugation of benzoic acid in rats. / Gregus, Z.; Fekete, Tibor; Halászi, Éva; Gyurasics, Ágnes; Klaassen, Curtis D.

In: Drug Metabolism and Disposition, Vol. 26, No. 11, 11.1998, p. 1082-1088.

Research output: Contribution to journalArticle

Gregus, Z, Fekete, T, Halászi, É, Gyurasics, Á & Klaassen, CD 1998, 'Effects of fibrates on the glycine conjugation of benzoic acid in rats', Drug Metabolism and Disposition, vol. 26, no. 11, pp. 1082-1088.
Gregus Z, Fekete T, Halászi É, Gyurasics Á, Klaassen CD. Effects of fibrates on the glycine conjugation of benzoic acid in rats. Drug Metabolism and Disposition. 1998 Nov;26(11):1082-1088.
Gregus, Z. ; Fekete, Tibor ; Halászi, Éva ; Gyurasics, Ágnes ; Klaassen, Curtis D. / Effects of fibrates on the glycine conjugation of benzoic acid in rats. In: Drug Metabolism and Disposition. 1998 ; Vol. 26, No. 11. pp. 1082-1088.
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