ON THE MECHANISM OF INHIBITION OF GLUCONEOGENESIS AND UREAGENESIS BY SODIUM BENZOATE

被引:22
作者
CYR, DM [1 ]
EGAN, SG [1 ]
BRINI, CM [1 ]
TREMBLAY, GC [1 ]
机构
[1] UNIV RHODE ISL,DEPT BIOCHEM & BIOPHYS,KINGSTON,RI 02881
关键词
D O I
10.1016/0006-2952(91)90328-3
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Synthesis of glucose from lactate and generation of urea from ammonia were inhibited when sodium benzoate was added to suspensions of rat hepatocytes. Assays with isolated mitochondria suggested pyruvate carboxylase and the N-acetyl-L-glutamate (NAG)-dependent carbamoylphosphate synthetase (CPS-I) as potential sites of inhibition for both pathways, owing to a shared dependency on aspartate efflux from the mitochondria and its subsequent conversion to oxaloacetate in the cytosol. Assays with isolated hepatocytes indicated inhibition to be initiated by accumulation of benzoyl CoA with a resultant depletion of free CoA and acetyl CoA. Measurements of adenine nucleotides showed that benzoate metabolism did not sufficiently after energy status to account for the observed inhibition. Consistent with these interpretations, acceleration of the conversion of benzoyl CoA to hippurate by the addition of glycine restored the levels of free CoA and acetyl CoA and the rates of gluconeogenesis and ureagenesis. Reduction of the levels of aspartate and glutamate, presumably by interference with the anapleurotic function of pyruvate carboxylase, most likely accounted for inhibition of gluconeogenesis by benzoate. Whether reduced flux through the urea cycle also contributed to inhibition of gluconeogenesis (by diminishing cytosolic conversion of aspartate to oxaloacetate) requires further study. Depression of glutamate and acetyl CoA to levels at or below the K(m) for NAG synthetase probably accounted for the observed inhibition of ureagenesis. Rates of urea production were observed to vary with changes in the levels of NAG, suggesting NAG-dependent CPS-I to be the primary site of inhibition of ureagenesis by benzoate.
引用
收藏
页码:645 / 654
页数:10
相关论文
共 53 条
[1]   EXCRETION OF HIPPURIC-ACID DURING SODIUM BENZOATE THERAPY IN PATIENTS WITH HYPERGLYCINEMIA OR HYPERAMMONEMIA [J].
BARSHOP, BA ;
BREUER, J ;
HOLM, J ;
LESLIE, J ;
NYHAN, WL .
JOURNAL OF INHERITED METABOLIC DISEASE, 1989, 12 (01) :72-79
[2]   INFLUENCE OF VALPROIC ACID ON HEPATIC CARBOHYDRATE AND LIPID-METABOLISM [J].
BECKER, CM ;
HARRIS, RA .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1983, 223 (02) :381-392
[3]   GLYCINE AVAILABILITY LIMITS MAXIMUM HIPPURATE SYNTHESIS IN GROWING-RATS [J].
BELIVEAU, GP ;
BRUSILOW, SW .
JOURNAL OF NUTRITION, 1987, 117 (01) :36-41
[4]  
BERGMEYER HU, 1965, METHODS ENZYMATIC ED, P328
[5]   TREATMENT OF EPISODIC HYPERAMMONEMIA IN CHILDREN WITH INBORN-ERRORS OF UREA SYNTHESIS [J].
BRUSILOW, SW ;
DANNEY, M ;
WABER, LJ ;
BATSHAW, M ;
BURTON, B ;
LEVITSKY, L ;
ROTH, K ;
MCKEETHREN, C ;
WARD, J .
NEW ENGLAND JOURNAL OF MEDICINE, 1984, 310 (25) :1630-1634
[6]   MITOCHONDRIAL UREA CYCLE ENZYMES IN RATS TREATED WITH SODIUM BENZOATE [J].
COLOMBO, JP ;
BACHMANN, C ;
PFISTER, U ;
GRADWOHL, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 151 (02) :872-877
[7]   ASSAY OF SHORT-CHAIN ACYL COENZYME-A INTERMEDIATES IN TISSUE-EXTRACTS BY HIGH-PRESSURE LIQUID-CHROMATOGRAPHY [J].
CORKEY, BE ;
BRANDT, M ;
WILLIAMS, RJ ;
WILLIAMSON, JR .
ANALYTICAL BIOCHEMISTRY, 1981, 118 (01) :30-41
[8]   POTENTIATION BY PYRIDOXILATE OF THE SYNTHESIS OF HIPPURATE FROM BENZOATE IN ISOLATED RAT HEPATOCYTES - AN APPROACH TO THE DETERMINATION OF NEW PATHWAYS OF NITROGEN-EXCRETION IN INBORN-ERRORS OF UREA SYNTHESIS [J].
COUDE, FX ;
COUDE, M ;
GRIMBER, G ;
PELET, A ;
CHARPENTIER, C .
CLINICA CHIMICA ACTA, 1984, 136 (2-3) :211-217
[9]  
COUDE FX, 1983, BIOCHEM J, V261, P233
[10]  
CYR D, 1989, THESIS U RHODE ISLAN