Diabetogenic action of alloxan-like compounds: cytotoxic effects of 5-hydroxy-pseudouric acid and dehydrouramil hydrate hydrochloride on rat pancreatic ? cells

Abstract

Summary.The effects on islet morphology and blood glucose concentration of intravenous administration of alloxan to rats have been compared with those of two new diabetogenic agents, 5-hydroxy-pseudouric acid (5-HPUA) and dehydrouramil hydrate hydrochloride (DHU). Administration of alloxan (0.35 mmol/kg) caused a classical triphasic change in blood glucose characterised by initial hyperglycaemia, subsequent hypoglycaemia and a delayed persistent hyperglycaemia. In contrast, 5-HPUA and DHU elicited persistent hyperglycaemia as early as 30 min after administration. Morphological evidence for degranulation, pyknosis, necrosis and widening of pericapillary spaces was obtained with all three agents. However, both 5-HPUA and DHU elicit considerably more rapid and extensive changes than alloxan, with evidence for extensive pyknosis occurring as early as 15 rain after administration of DHU and 5-HPUA compared with 24 h for alloxan. The more marked potency of DHU and 5-HPUA may be at least partially attributable to the greater stability of these agents compared with alloxan, since solutions of DHU or 5-HPUA kept for 15 min prior to administration retained full diabetogenic activity, whereas similar treatment of alloxan solution completely abolished its diabetogenic activity. Since both 5-HPUA and DHU are potential metabolites of uric acid, their marked diabetogenic potency raises the possibility of a role for uric acid metabolites in the pathogenesis of diabetes mellitus.Key words: Alloxan, dehydrouramil, 5-hydroxy-pseudouric acid, diabetes.The structural elucidation of intermediates in the oxidative breakdown of uric acid [1][2][3] have helped to unravel the chemistry and biological effects of alloxan-like compounds derived from uric acid. Recently we reported the production of permanent diabetes in rats by the intravenous administration of either 5-hydroxy-5-ureido-2,4,6(1 H,3H,5H)-pyrimidinetrione (5-hydroxypseudouric acid, 5-HPUA) or 5-amino-5-hydroxy-2,4,6 (1H,3H,5H)-pyrimidinetrione hydrochloride (dehydrouramil hydrate hydrochloride, DHU) [4,5]. These new compounds were among the most active diabetogenic agents: in comparison with alloxan, there is a twofold difference in EDs0 values; moreover the EDs0 of both alloxan-like compounds corresponded to a dose of alloxan which does not in itself cause diabetes. Studies of DHU on isolated rat islets of Langerhans in vitro have shown a spectrum of acute effects on the fl cell similar in many respects to that of alloxan [6]. Substantial inhibition of glucose-stimulated insulin release was achieved at a concentration (0.5 mmol/1) of DHU that did not affect islet glucose oxidation or ATP content. Thus a derangement of energy metabolism is not the primary cause for impairment of insulin release. These findings may serve to renew a plausible hypothesis for the aetiology of diabetes mellitus, that a substance biogenetically related to uric acid may have an alloxan-like action on the islet fl cells [7]. Since the mechanism of production of alloxan diabetes is still obscure, a ca...

Total plasma antioxidants in first-degree relatives of patients with insulin-dependent diabetes

“…Thus, ascorbate efficacy as a scavenger involves its oxidation via ascorbyl radical to dehydro-ascorbic acid that itself is diabetogenic (Patterson, 1950). More recently the diabetogenic activity of alloxan-like derivatives of uric acid, like 5-hydroxypseudouric acid and uric acid glycol, was found to elicit almost complete 3-cell destruction in rats (Tait et al, 1983;Dominis et al, 1984). Urate, an endogenous free radical scavenger, operates probably via electron transfer (Maples and Mason, 1988), and its degradation during antioxidative processes might originate the production of different uric acid derivatives (Grootveld and Halliwell, 1987), including 3-cytotoxic alloxanlike compounds (Ashcroft et al, 1986).…”

Structure‐activity relationships of alloxan‐like compounds derived from uric acid

“…Five doses of each drug (with 12 rats at each dose) were used and the dose required to produce diabetes in 50% of animals (ED_0) was estimated graphically (Lithfield & Wilcoxon, 1949). Additional information was obtained by examination of histological changes and islet morphology (Dominis et al, 1984); islets from each experimental group were analysed with respect to the normal appearance of the P-cells, their degree of degranulation, picnosis and necrosis.…”

“…Five doses of each drug (with 12 rats at each dose) were used and the dose required to produce diabetes in 50% of animals (ED_0) was estimated graphically (Lithfield & Wilcoxon, 1949). Additional information was obtained by examination of histological changes and islet morphology (Dominis et al, 1984); islets from each experimental group were analysed with respect to the normal appearance of the P-cells, their degree of degranulation, picnosis and necrosis. Table 1 shows the results obtained after a single administration of a range of alloxan-like compounds derived from uric acid: for completion, Table 1 includes data from previous (Bruckmann & Wertheimer, 1947;Poje et al, 1983) as well as the present study.…”

“…Alloxan-like derivatives of uric acid exerted strong cytotoxic effects upon P-cells of rat pancreatic islets of Langerhans, which revived interest in the plausible hypothesis postulating that aberrations in purine metabolism could have relevance to the aetiology of diabetes mellitus Poje et al, 1983;Tait et al, 1983;Dominis et al, 1984) and re-opened the question of alternative uricolytic pathways. It is of interest in this connection that a report has appeared describing the occurrence of an unidentified urinary excretion product in animals and in man, which, on alkaline hydrolysis, yielded mesoxalic acid (Paley et al, 1953 Recent findings (Malaisse et al, 1982) demonstrated that the selective cytotoxicity of alloxan to pancreatic P-cells may result from the conjunction of two features: a rapid cellular uptake of the drug and an exquisite sensitivity of the P-cell to peroxides, itself attributable to low peroxidase activity.…”