Does hepatic ATP depletion impair glycine conjugation in vivo?
Conjugation with glycine, a reaction important in the elimination of carboxylic acids (e.g. benzoic and salicylic acids), takes place in hepatic mitochondria and uses ATP, coenzyme A, and glycine. Although normal ATP supply does not limit glycine conjugation in vivo (Gregus, Z., et al., Drug Metab. Dispos. 20, 234, 1992), ATP deficiency may impair it. This hypothesis was tested by examining the effect of ATP depletors (oligomycin, fructose, and ethionine) on glycine conjugation and elimination of benzoic acid in rats. Pretreatment with the mitochondrial ATP synthesis inhibitor oligomycin (0.5-2 mg/kg, intraportally) decreased glycine conjugation of benzoic acid markedly and in a dose-dependent manner, as indicated by the delayed elimination of benzoate and delayed appearance of benzoylglycine in blood. Oligomycin also dramatically diminished urinary excretion of benzoylglycine, because it inhibited not only formation of benzoylglycine from benzoate, but also the renal transport of benzoylglycine. Treatment with fructose (a consumer of both cytosolic and mitochondrial ATP) or ethionine (a consumer of cytosolic ATP) depleted hepatic ATP from approximately 2.5 micromol/g to levels comparable with those observed after administration of 1 mg/kg oligomycin (approximately 1.2 micromol/g). Despite this, elimination of benzoate and formation of benzoylglycine were decreased less by fructose than by oligomycin and only negligibly by ethionine. ATP depletors did not influence hepatic glycine levels, and only oligomycin lowered coenzyme A levels in liver. However, the oligomycin-induced decline of hepatic coenzyme A levels was delayed, contrary to impairment of glycine conjugation, which was almost immediate. In summary, impairment of benzoylglycine formation by ATP depletors apparently correlates with their capacity to diminish ATP levels in hepatic mitochondria (i.e. at the site of glycine conjugation). These observations suggest that limited availability of mitochondrial (but not cytosolic) ATP reduces glycine conjugation capacity. Therefore, mitochondrium toxic agents and pathological mitochondrial injuries acting in liver may compromise glycine conjugation by decreasing ATP supply.
Gregus
Z
Z
Department of Pharmacology, University Medical School of Pécs, Hungary.
Fekete
T
T
Halászi
E
E
Klaassen
C D
CD
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism; D019817:Benzoic Acid; D002851:Chromatography, High Pressure Liquid; D003065:Coenzyme A / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005001:Ethionine / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D006207:Half-Life; D006626:Hippurates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D009840:Oligomycins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000963:Antimetabolites; D001565:Benzoates; D004791:Enzyme Inhibitors; D006626:Hippurates; D009840:Oligomycins; D005632:Fructose; D000255:Adenosine Triphosphate; D019817:Benzoic Acid; D003065:Coenzyme A; C030514:hippuric acid; D005998:Glycine; D005001:Ethionine