Effects of age on the homeostasis and turnover of endogenous inorganic sulfate and hepatic ATP in male F-344 rats

Hepatic function declines with age and leads to alterations in sulfation. Sulfation involves the transfer of the sulfate group from the activated form of sulfate, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to the substrate. The formation of the co-substrate PAPS requires both inorganic sulfate and two adenosine triphosphate (ATP) molecules. In order to determine the role of inorganic sulfate and ATP in age-related alterations in sulfation, the following experiments were conducted in young (5-6 mo.) and old (21-22 mo.) male F-344 rats. The homeostasis of endogenous inorganic sulfate was examined by measuring the renal clearance of sulfate over a wide plasma concentration range. The plasma sulfate concentrations and the turnover of sulfate were unchanged by advanced age, suggesting that the age-related changes in sulfation cannot be attributable to alterations in inorganic sulfate availability. However, the baseline excretion rate of sulfate was lower in old rats. At the lowest plasma sulfate concentrations (after acetaminophen administration), old rats continued excreting sulfate, while sulfate excretion was zero in young rats. Since the excretion rate of sulfate is lower, it is possible that there are alterations in the metabolic fate of inorganic sulfate in old rats. There also seems to be alterations in sulfate reabsorption with age at low plasma sulfate concentrations. In vitro analyses of renal tissue viability demonstrated that there was a significant decrease in p-aminohippurate uptake, suggesting an age-related decrease in certain active transport processes. Tissue nonprotein sulfhydryls as a measure of glutathione were increased with age. Hepatic ATP levels were quantified noninvasively using [31]P in vivo NMR spectroscopy. L-Ethionine was used to deplete ATP. ATP was decreased by 35% in the older rats; whereas, it remained unchanged in the younger rats after L-ethionine administration. This suggested that older rats are more sensitive to the ATP depleting effects of L-ethionine which could either be due to decreased ATP levels in the liver, or decreased rate of resynthesis of ATP de novo after L-ethionine administration. The effects of L-ethionine were also examined in vitro in kidney slices. L-Ethionine administration increased nonprotein sulfhydryls in the kidney.