BASIC PHOSPHOLIPASES A₂ FROM Bothrops sp VENOMS: UNDERSTANDING A COMPLEX PHARMACOLOGICAL PROFILE INVOLVED IN LOCAL TISSUE DAMAGE

GUTIÉRREZ, J.M.(1), CHACUR, M.(2), ZULIANI, J. P.(3); LONGO, I.(2) LOMONTE, B.(1), PICOLO, G.(2), TEIXEIRA, C.F.P.(3), CURY, Y.(2)

(1)Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica, and Laboratorios de (2) Fisiopatología and (3)Farmacología, Instituto Butantan, Sao Paulo, Brasil

Many Bothrops sp venoms contain basic phospholipases A₂ (PLA₂).  Some of them are catalytically-active Asp-49 variants, whereas others are Lys-49 PLA₂s  devoid of enzymatic activity.  Although these proteins were originally described as ‘myotoxins’, further studies have documented a more complex pharmacological profile.  Besides myotoxicity, they induce pain and promote a complex inflammatory response.  Moreover, they exert a broad cytolytic activity in vitro, including bactericidal activity, and some of them are highly lethal when injected into the brain, also inducing an anticoagulant effect. The mechanisms involved in myotoxic, hyperalgesic and proinflammatory activities of basic PLA₂s isolated from the venom of B. asper have been investigated.  Myotoxicity depends on the ability of these toxins to interact with acceptor sites in the sarcolemma, followed by disorganization of the bilayer and prominent Ca²⁺ influx.  Catalytic activity is not a strict requirement for myotoxicity and, in the case of Lys-49 PLA₂s, membrane damage is due to a cationic-hydrophobic region located at the C-terminus.  Catalytic activity of Asp-49 PLA₂s potentiates such membrane-damaging effect.  Hyperalgesia induced by Asp-49 and Lys-49 PLA₂s is mediated by histamine, bradykinin, TNF-a and IL-1.  In the case of Lys-49 variants, sympathomimetic amines and cyclooxygenase-derived eicosanoids are also involved.  Catalytic activity is required in Asp-49 PLA₂-induced hyperalgesia, whereas the molecular region responsible for cytotoxicity is involved in Lys-49 PLA₂-induced algogenic effect.  Both types of PLA₂s elicit an inflammatory infiltrate associated with the expression of a number of adhesion molecules.  They also promote the synthesis of leukotriene B₄, thromboxane B₂, IL-6 and matrix metalloproteinases.  Incubation of B. asper PLA₂s with macrophages in vitro stimulates phagocytosis and the production of H₂O₂ and NO.  Basic PLA₂s from Bothrops sp venoms play a prominent role in the local tissue alterations characteristic of these envenomations.

Supported by FAPESP, Vicerrectoría de Investigación (Universidad de Costa Rica) and NeTropica.

CORRESPONDENCE TO:

José María Gutiérrez Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica, AC E-mail: jgutierr@icp.ucr.ac.cr