Photodynamic drug action on isolated rat pancreatic acini. Mobilization of arachidonic acid and prostaglandin production.
Chloro-aluminium phthalocyanine sulphonate (SALPC) when photon-activated generates singlet oxygen, elicits amylase release and causes plasma membrane permeabilization of pancreatic acinar cells (Matthews and Cui, Biochem Pharmacol 39: 1444-1457, 1990). Amylase release precedes membrane permeabilization suggesting that the initial release of amylase may be due to direct stimulation by singlet oxygen of secretagogue receptors or their coupled guanine nucleotide binding proteins (G-proteins) and effector systems including phospholipase A2 (PLA2). The aim of the experiments reported here was to establish the extent to which PLA2 activation, arachidonic acid mobilization, and prostaglandin production are involved in the photon-induced action of SALPC on dispersed, perifused acini isolated from the rat pancreas. The mobilization of arachidonic acid by a major secretory stimulant of pancreatic exocrine cells, cholecystokinin octapeptide, was also assessed: it produced a time- and concentration-dependent (10(-10)-10(-6) M) stimulation of arachidonic acid output from acini prelabelled with [1-14C]arachidonic acid. In contrast, the kinetics of arachidonic acid mobilization with photon-activated SALPC 1 microM, 4500 or 18,400 lux light intensity (lambda > 570 mm), was biphasic, an intensity-dependent stimulation being preceded by a more immediate initial inhibition of output. Light activation of SALPC and singlet oxygen generation may evoke the stimulatory phase 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 microM caused a 2.9-, 33- and 5-fold increase, respectively, in arachidonic acid output. However, not only was the arachidonate stimulation delayed in response to SALPC but in other experiments designed to gain more insight into the turnover of arachidonic acid and its metabolites, the photodynamic release of 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 microM. It is therefore likely that the rapid initial photodynamic release of amylase from pancreatic acini induced by SALPC is mediated by activation of the signal transduction pathway involving the release of intracellular calcium; arachidonic acid mobilization and prostanoid production may then be linked to the longer-term, cytolytic action of SALPC, especially in tumour cells.
al-Laith
M
M
Department of Pharmacology, University of Cambridge, U.K.
Matthews
E K
EK
Cui
Z J
ZJ
D000681:Amylases / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008027:Light; D008555:Melitten / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012969:Sodium Fluoride / Q000494:pharmacology
D007211:Indoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; C052736:chloroaluminum tetrasulfophthalocyanine; D008555:Melitten; D016718:Arachidonic Acid; D000001:Calcimycin; D012969:Sodium Fluoride; D000681:Amylases; D015232:Dinoprostone