[Effect of lysine clonixinate and indomethacin on lipoxygenase and cyclooxygenase activity in colon isolated from cancer patients].
The non-steroidal anti-inflammatory drugs (NSAIDS) induced ulcerations in the gastrointestinal tract are possibly associated with the reduction in prostaglandin (PGs) synthesis due to the inhibition of cyclooxygenase. On the other hand, it has been shown that 5-lipooxygenase products (5-LO) are ulcerogenic agents. In some cases, the utilization of NSAIDS stimulates 5-LO pathway to an excess of arachidonic acid because of cyclooxygenase inhibition. In these cases, the damage produced by NSAIDS is greater, since not only the cytoprotective PGs decrease but also the products of 5-LO are increased. The object of the present paper was to study the effects of lysine clonixinate (LC) and indomethacin (INDO) on PGs and 5-HETE synthesis. The concentrations used of LC (4 and 6 micrograms/ml) and INDO (0.035 micrograms/ml and 0.35 micrograms/ml) correspond to the plasmatic values reached with oral therapeutic doses for both drugs. The results show that in no case did LC reduce the production of PGE2. On the contrary INDO inhibited significantly the synthesis of PGe2. It is interesting to mention that LC 4 and 6 micrograms/ml inhibited drastically the production of 5-HETE. Only with the higher concentration of INDO did we observe a similar effect. These results may indicate an inhibitory action on 5-LO, the first enzyme in the metabolic pathway of arachidonic acid in the production of HETEs and LTS. We conclude that LC in therapeutic doses has a mechanism of action different from the classical NSAIDS. The data obtained in this study could explain the low incidence in gastrointestinal lesions with LC.
Franchi
A
A
Centro de Estudios Farmacológicos y Botánicos (CEFYBO).
Di Girolamo
G
G
de los Santos
A R
AR
Marti
M L
ML
Gimeno
M A
MA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D003106:Colon / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy; D016861:Cyclooxygenase Inhibitors; D005753:Gastric Mucosa / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008239:Lysine / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D008239:Lysine; D007213:Indomethacin