Effect of anthracyclines on phospholipase A2 activity and prostaglandin E2 production in rat gastric mucosa.
The purpose of this study was to investigate in rats the effects of three anthracyclines, pirarubicin, doxorubicin and epirubicin on gastric prostaglandin E2 (PGE2) metabolism and phospholipase A2 (PLA2, EC 3.1.1.4) activity. The level of the membrane precursor, arachidonic acid, and the stability of the membrane were investigated by analysis of the composition of fatty acids. Enzymatic activities involved in the turnover of membrane phospholipids such as lysophospholipase (LPase, EC 3.1.1.5) and acyl-CoA lysophosphatidylcholine: acyltransferase (ACLAT, EC 2.3.1.23), and in the detoxification of lipid hydroperoxides, selenium-dependent glutathione-peroxidase (GSH-PX, EC 1.11.1.9) were measured after injection of the drugs for 4 consecutive days. Pirarubicin does not give rise to any changes in these activities but doxorubicin and epirubicin decreased PGE2 production and the activities of PLA2, LPase and ACLAT. GSH-PX activity was not changed by any of the drugs. The decrease in PLA2 activity does not seem to be related to variations in membrane lipid composition because the total phospholipids content was unchanged. The P/S (polyunsaturated/saturated) ratio increased in the doxorubicin group and decreased in the epirubicin group, and the unsaturation index was moderately modified. Arachidonic acid was increased only in the doxorubicin group. In vitro, PLA2 activity was not inhibited by the three drugs in the micromolar range. A marked inhibition was observed at 2.5 mM for pirarubicin and at 1.0 mM for doxorubicin and epirubicin. The Lineweaver-Burk representation showed that these inhibitions were of an uncompetitive type. Pirarubicin may therefore be considered to be an anthracycline without marked side-effects on gastric mucosa. However, the in vitro inhibition of PLA2 activity by anthracyclines does not fully explain the in vitro decrease in PLA2 specific activity observed after doxorubicin and epirubicin treatment, and in this context membrane structure modifications unconnected with the lipid composition can not be excluded. In vivo these phenomena may affect PGE2 synthesis, whose level was lower in the doxorubicin and epirubicin groups than in control group.
Grataroli
R
R
INSERM U130, Marseille, France.
Leonardi
J
J
Chautan
M
M
Lafont
H
H
Nalbone
G
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology; D005227:Fatty Acids / Q000032:analysis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D005227:Fatty Acids; D015251:Epirubicin; D004317:Doxorubicin; C027260:pirarubicin; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone