LAZAROIDS PROTECT ISOLATED RAT PANCREATIC ACINAR-CELLS AGAINST DAMAGE-INDUCED BY FREE-RADICALS

Lazaroids, 21-aminosteroids without gluco-and mineralocorticoid activi ty, protect against oxidative injury in nervous system cells and may t herefore also have a potential for treatment of pancreatitis, where ox idative stress contributes to cell injury. The present study evaluates the protective potential of the lazaroids U-78518F, U-74500A, and U-7 4389F against damage to isolated pancreatic acinar cells exposed to tw o models of oxidative stress: (a) a XOD/HX model, consisting of xanthi ne oxidase, hypoxanthine, and chelated FeCl3; and (b) an ADP/Fe model, consisting of FeSO4 and the reducing agent ADP. Both models caused ti me-dependent cell injury as assessed by uptake of trypan blue and rele ase of lactate dehydrogenase. Short-term peak production of free radic als in the XOD/HX model-as monitored by the deoxyribose assay-was more injurious to cells than continuous radical generation at lower levels in the ADP/Fe model. In general, lazaroids at 1-10 mu M reduced oxida tive damage and deoxyribose oxidation in both models.The degree of red uction of cell damage and deoxyribose oxidation depended on the type a nd concentration of the lazaroid and the model used. Lazaroid concentr ations <0.1 mu M were ineffective, and concentrations >50 mu M even ac celerated cell injury, although lazaroids still served as scavengers a t high concentrations. At least part of the noxious effects of high la zaroid concentrations is due to nonspecific membrane damage because th ese concentrations caused cell injury also in the absence of oxidative stress. The limited range of protective concentrations has to be obse rved in further in vivo studies. Interestingly, acinar cells in the ab sence of lazaroids also reduced radical-induced deoxyribose degradatio n. Thus, despite its susceptibility to oxidative stress, the pancreati c acinar cell itself acts as a potent radical scavenger.