Aria pharmacol. ei zyxwvutsrqp ioxicol. 1983, zyxwvuts 53, 392-400. From the Department of Medical Cell Biology, Uppsala University, P. 0. Box 571, S-751 23 Uppsala, Sweden zy Streptozotocin-induced Impairment of Islet B-Cell Metabolism and its Prevention by a Hydroxyl Radical Scavenger and Inhibitors of Poly(ADP-ribose) synthetase BY Stellan Sandler, Michael Welsh and Arne Andersson (Received April 7, 1983; Accepted July 13, 1983) Abstract: The possible protective effects zyxwvut in viiro of the hydroxyl radical scavenger dimethyl urea (6 mg/ml) and the poly(ADP-rib0se)synthetase inhibitors theophylline (5 mM) and nicotinamide (0.75 mg/ml) against streptozotocin (SZ) induced deterioration of islet metabolism were investigated using isolated mouse pancreatic islets. All these compounds counteracted to different extents the deleterious effects of SZ (4.4 mM) on glucose- stimulated (pro)insulin biosynthesis, dimethyl urea protecting least. No protective effects against SZ were obtained by adding 16.7 mM glucose or 5 mM dibuturyl CAMP. The islet NADHSNAD content decreased drastically when exposed to SZ. Again, nicotinamide and theophylline protected better against the SZ-effects on pyridine nucleotides than dimethyl urea. Furthermore, the maintenance of a linear rate of oxygen uptake was lost after SZ-exposure of the islets, and there was no increase of the respiratory rate when these islets were challenged with high glucose. Also in these islet respiratory studies a partial or total protection by dimethyl urea, theophylline and nicotinamide against SZ was observed. In perifusion experiments SZ rapidly decreased insulin release together with a slightly delayed increased radioactive nucleotide efflux. Later (about 20 min.) a massive leakage of both radioactive nucleotides and insulin occurred in most of the experiments. It is concluded that all the observed impairments of islet metabolism after SZ-exposure can be related to islet NAD depletion, which may depend on poly(ADP-rib0se)synthetas.e activation due to DNA damage. The SZ-induced DNA injury may be mediated by free radicals as suggested by the protective effects of dimethyl urea. Keywords: Pancreatic islets zyxwvutsr - streptozotocin - poly(ADP4bose)synthetase - dimethyl urea. Despite its wide use as a B-cell toxic agent, the exact mechanism(s) by which streptozotocin (SZ) causes islet B-cell destruction is still unknown. It has been known for long, that SZ depletes the islet NAD content and that nicotinamide can protect against SZ (Schein et a/. 1967; Ho & Hashim 1972; Schein et a/. 1973; Hinzetal. 1973; Gunnarsson et zyxwvuts al. 1974; Akpan et al. 1982). Moreover, Okamoto and coworkers recently demonstrated an increased ac- tivity of polyadenosine diphosphoribose (poly (ADP-rib))synthetase in islets exposed to SZin vivo and in vitro (Yamamoto et zyxwvut a/. 1981a; Okamoto 1981; Yamamotoetal. 1981b; Uchigataetal. 1982). This enzyme uses NAD as a substrate, is involved in DNA repair and is activated by single strand breaks of DNA. It has therefore been suggested that activation of poly(ADP-rib)synthetase after SZ- induced DNA-injury is the major cause of NAD depletion which ultimately leads to B-cell death. The primary trigger of this sequence of events is, however, not yet known. In a recent report we demonstrated that the hydroxyl radical scavenger, dimethyl urea (DMU) partially protects mice against SZ-induced hyperglycemia and also reduces inhibition of glucose-stimulated (pro)insulin bio- synthesis effected by in vitro exposure of islets to SZ