M. Allaith et al., PHOTODYNAMIC DRUG-ACTION ON ISOLATED RAT PANCREATIC ACINI - MOBILIZATION OF ARACHIDONIC-ACID AND PROSTAGLANDIN PRODUCTION, Biochemical pharmacology, 46(4), 1993, pp. 567-573
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.