Lipoxygenase-mediated pro-radical effect of melatonin via stimulation of arachidonic acid metabolism

Journal Article · Wed Jul 15 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.05.011· OSTI ID:21272604

Radogna, F ^[1]; Sestili, P; Martinelli, C; Paolillo, M ^[2]; Paternoster, L; Albertini, M C; Accorsi, A ^[3]; Gualandi, G ^[4]

---

1. Dipartimento di Biologia, Universita di Roma Tor Vergata, via Ricerca Scientifica, 1 00133 Roma (Italy)
2. Istituto di Ricerca sull'Attivita Motoria (Italy)
3. Istituto di Chimica Biologica, Universita di Urbino Carlo Bo (Italy)
4. DABAC, Universita della Tuscia (Italy)

We have shown that melatonin immediately and transiently stimulates intracellular free radical production on a set of leukocytes, possibly as a consequence of calmodulin binding. We show here that melatonin-induced ROS are produced by lipoxygenase (LOX), since they are prevented by a set of LOX inhibitors, and are accompanied by increase of the 5-LOX product 5-HETE. LOX activation is accompanied by strong liberation of AA; inhibition of Ca{sup 2+}-independent, but not Ca{sup 2+}-dependent, phospholipase A2 (PLA2), prevents both melatonin-induced arachidonic acid and ROS production, whereas LOX inhibition only prevents ROS, indicating that PLA2 is upstream with respect to LOX, as occurs in many signaling pathways. Chlorpromazine, an inhibitor of melatonin-calmodulin interaction, inhibits both ROS and arachidonic acid production, thus possibly placing calmodulin at the origin of a melatonin-induced pro-radical pathway. Interestingly, it is known that Ca{sup 2+}-independent PLA2 binds to calmodulin: our results are compatible with PLA2 being liberated by melatonin from a steady-state calmodulin sequestration, thus initiating an arachidonate signal transduction. These results delineate a novel molecular pathway through which melatonin may participate to the inflammatory response.

• OSTI ID: 21272604
• Journal Information: Toxicology and Applied Pharmacology, Vol. 238, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.05.011; PII: S0041-008X(09)00201-4; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARACHIDONIC ACID
CALCIUM IONS
CALMODULIN
CHLORPROMAZINE
ENZYME INHIBITORS
INFLAMMATION
LEUKOCYTES
MELATONIN
METABOLISM
OXYGENASES
RADICALS
STIMULATION