Search

Summary: Rabbit antibody to human liver arginase was used to examine the immunologic characteristics of arginase in red blood cells (RBC), liver, kidney, brain, and gastrointestinal tract from normal adults and from patients with hyperargininemia. Greater than 90% of the argitiase in RBC and liver was precipitated by this antibody whereas only 50% of the arginase in kidney, brain,, and gastrointestinal tract reacted with it.Two siblings and a third patient withchyperargininemia were found to have immunoreactive arginase protein in their RBC that was enzymatically inactive. The amount of arginase protein approximated that found in RBC from normal individuals.A kidney biopsy obtained from one of the patients with hyperargininemia had arginase activity 4-5-fold greater than that found in normal kidney biopsy material. Double immunodiffusion and precipitation-inhibition studies demonstrated two types of arginase protein in this patient's kidney: one enzymatically inactive and precipitated by the antibody, and one enzymatically active but not precipitated by the antibody. These data, in conjunction with biochemical data reported previously demonstrate that there are two gene loci determining arginase in man.

We have examined and characterized the regulation by glucocorticoids of the levels of arginase and argininosuccinate synthetase in two rat hepatoma cell lines (H4-II-E-C3 and MH1C1). Hydrocortisone elevates the activity of both enzymes in a time- and dose-dependent fashion. This effect was blunted markedly by small amounts of ethanol (0.1 to 0.9% [v/v]) and blocked substantially by a high molar excess of the "anti-inducer" steroid fluoxymesterone. The other "optimal" inducers dexamethasone and corticosterone were as effective as hydrocortisone in elevating the levels of these enzymes at saturating concentrations. Inhibition of these stimulations by cycloheximide indicated that ongoing cellular protein synthesis was required for both effects, and the admixture of extracts from fully stimulated and basal cells gave no evidence for the existence of direct inhibitors or activators of either enzyme. The results corroborate findings from earlier whole-animal studies and provide evidence for the following conclusions. (i) This stimulation by hydrocortisone of urea-cycle enzymes in the cultured hepatoma cells is mediated by a classical glucocorticoid mechanism involving initial binding to specific cytoplasmic steroid receptors and the eventual accumulation of new enzyme molecules. (ii) These cell lines thus constitute valid experimental models for use in further detailed studies on the molecular mechanism(s) through which glucocorticoids and intermediary metabolites effect a selective modulation of arginase and argininosuccinate-synthetase gene expression in the differentiated mammalian liver.

Summary: A female and a male sibling aged 15 and 8 yr developed almost normally for 3 yr, then gradually deteriorated intellectually and physically. Both patients showed marked hyperargininuria (up to 370 times normal), prominent lysinuria, cystinuria, and ornithinuria, and a milder generalized amino aciduria. In plasma, arginine was 600–1000 µM (4–7 times normal), but other amino acids were not increased. The levels did not change in response to increased protein intake from 1–3 g/kg/day. In cerebrospinal fluid (CSF), arginine was 70–100 µM (3–5 times normal) and numerous other amino acids were also high. Plasma ammonia was generally normal, but rose to 250 µg/dl (5 times normal) after increased protein intake and, occasionally, other stresses. The erythrocyte arginase activity level was <1% of normal and half normal in the mother and three healthy siblings. White blood cell arginase activity was less than 5% of the lowest normal control. Liver obtained at open biopsy in the older sibling was deficient in arginase activity (1.5% of normal), but had levels of the other four urea cycle enzymes that were within the normal range. Electron microscopic and histochemical studies revealed patchy severe hydropic changes, increased cellular glycogen, normal mitochondria, and dilated endoplasmic reticulum.Speculation: The pathogenesis of the neurologic abnormalities in patients with arginase deficiency may in part be the perturbation of intra-cellular amino acid levels secondary to the elevated levels of arginine.