EFFECTS OF FIBRATES ON THE GLYCINE CONJUGATION OF BENZOIC-ACID IN RATS

In the course of glycine conjugation, benzoic acid is successively con verted into benzoyl-CoA and benzoylglycine by mitochondrial enzymes (i .e. benzoyl-CoA synthetase and benzoyl-CoA/glycine IV-acyltransferase, respectively), utilizing ATP, CoA, and glycine. Large doses of benzoa te deplete CoA from the liver, suggesting that the supply of CoA may l imit 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 be zafibrate (2.5 mmol/kg of feed, for 10 days) increased hepatic CoA lev els 8-10-fold, while not affecting hepatic ATP levels; only fenofibrat e elevated, albeit moderately, the concentration of glycine in liver. Hepatic mitochondria isolated from fibrate-fed rats, compared with tho se from controls, exhibited unchanged benzoyl-CoA synthetase activity but higher benzoyl-CoA hydrolase and lower benzoyl-CoA/glycine N-acylt ransferase activities. Feeding with either fibrate increased liver mas s by 50-60%. Control and fibrate-fed rats were administered benzoate a t 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 les ser extent bezafibrate-fed animals, exhibited increased glycine conjug ation capacity, as indicated by faster disappearance of benzoate from the blood and appearance of benzoylglycine in the blood and urine, com pared 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 n ot enhanced in liver slices from fibrate-fed rats; moreover, it was lo wer than control levels in slices from bezafibrate-fed animals. Bezafi brate, but not fenofibrate, given to rats in a single dose (0.5 mmol/k g, ip) decreased the elimination and glycine conjugation of benzoate, indicating that bezafibrate is a direct inhibitor of glycine conjugati on. In summary, fibrates influence glycine conjugation in a complex ma nner. Some fibrate-induced alterations (i.e. increased benzoyl-CoA hyd rolase and decreased glycine transferase activities and direct inhibit ion by bezafibrate) can potentially hinder conjugation of benzoate wit h glycine, thus precluding conclusions regarding whether increased CoA availability enhances glycine conjugation. Fibrate-induced hepatomega ly appears to significantly contribute to the increased glycine conjug ation capacity of rats treated with fenofibrate or bezafibrate.