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

Lazaroids, 21-aminosteroids without gluco-and mineralocorticoid activity, protect against oxidative injury in nervous system cells and may therefore also have a potential for treatment of pancreatitis, where oxidative stress contributes to cell injury. The present study evaluates the protective potential of the lazaroids U-78518F, U-74500A, and U-74389F against damage to isolated pancreatic acinar cells exposed to two models of oxidative stress: (a) a XOD/HX model, consisting of xanthine oxidase, hypoxanthine, and chelated FeCl3; and (b) an ADP/Fe model, consisting of FeSO4 and the reducing agent ADP. Both models caused time-dependent cell injury as assessed by uptake of trypan blue and release of lactate dehydrogenase. Short-term peak production of free radicals 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 oxidative damage and deoxyribose oxidation in both models.The degree of reduction of cell damage and deoxyribose oxidation depended on the type and concentration of the lazaroid and the model used. Lazaroid concentrations <0.1 mu M were ineffective, and concentrations >50 mu M even accelerated cell injury, although lazaroids still served as scavengers at high concentrations. At least part of the noxious effects of high lazaroid concentrations is due to nonspecific membrane damage because these concentrations caused cell injury also in the absence of oxidative stress. The limited range of protective concentrations has to be observed in further in vivo studies. Interestingly, acinar cells in the absence of lazaroids also reduced radical-induced deoxyribose degradation. Thus, despite its susceptibility to oxidative stress, the pancreatic acinar cell itself acts as a potent radical scavenger.