PHOTODYNAMIC DRUG-ACTION ON ISOLATED RAT PANCREATIC ACINI - MOBILIZATION OF ARACHIDONIC-ACID AND PROSTAGLANDIN PRODUCTION

Chloro-aluminium phthalocyanine sulphonate (SALPC) when photon-activat ed generates singlet oxygen, elicits amylase release and causes plasma membrane permeabilization of pancreatic acinar cells (Matthews and Cu i, Biochem Pharmacol 39: 1444-1457, 1990). Amylase release precedes me mbrane permeabilization suggesting that the initial release of amylase may be due to direct stimulation by singlet oxygen of secretagogue re ceptors or their coupled guanine nucleotide binding proteins (G-protei ns) and effeCtor systems including phospholipase A2 (PLA2). The aim of the experiments reported here was to establish the extent to which PL A2 activation, arachidonic acid mobilization, and prostaglandin produc tion are involved in the photon-induced action of SALPC on dispersed, perifused acini isolated from the rat pancreas. The mobilization of ar achidonic acid by a major secretory stimulant of pancreatic exocrine c ells, cholecystokinin octapeptide, was also assessed: it produced a ti me- and concentration-dependent (10(-10)-10(-6)M) stimulation of arach idonic acid output from acini prelabelled with [1-C-14]arachidonic aci d. In contrast, the kinetics of arachidonic acid mobilization with pho ton-activated SALPC 1 muM, 4500 or 18,400 lux light intensity (lambda > 570 mm), was biphasic, an intensity-dependent stimulation being prec eded by a more immediate initial inhibition of output. Light activatio n of SALPC and singlet oxygen generation may evoke the stimulatory pha se of arachidonic acid release by an action on G-proteins, or by PLA2 activated directly, or via calcium influx, because NaF 20 mM, mellitin 2 mg/mL and the calcium ionophore A23187 1 muM caused a 2.9-, 33- and 5-fold increase, respectively, in arachidonic acid output. However, n ot only was the arachidonate stimulation delayed in response to SALPC but in other experiments designed to gain more insight into the turnov er of arachidonic acid and its metabolites, the photodynamic release o f amylase preceded maximum prostaglandin E2 (PGE2) output and amylase release was completely unaffected when PGE2 production was blocked by the cyclo-oxygenase inhibitor, indomethacin 10 muM. It is therefore li kely that the rapid initial photodynamic release of amylase from pancr eatic acini induced by SALPC is mediated by activation of the signal t ransduction pathway involving the release of intracellular calcium; ar achidonic acid mobilization and prostanoid production may then be link ed to the longer-term, cytolytic action of SALPC, especially in tumour cells.