Intraspecies variation in the venom of the rattlesnake Crotalus simus from Mexico: Different expression of crotoxin results in highly variable toxicity in the venoms of three subspecies

The composition and toxicological profile of the venom of the rattlesnake Crotalus simus in Mexico was analyzed at the subspecies and individual levels. Venoms of the subspecies C. s. simus, C. s. culminatus and C. s. tzabcan greatly differ in the expression of the heterodimeric neurotoxin complex ‘crotoxin’, with highest concentrations in C. s. simus, followed by C. s. tzabcan, whereas the venom of C. s. culminatus is almost devoid of this neurotoxic PLA2. This explains the large variation in lethality (highest in C. s. simus, which also exerts higher myotoxicity). Coagulant activity on plasma and fibrinogen occurs with the venoms of C. s. simus and C. s. tzabcan, being absent in C. s. culminatus which, in turn, presents higher crotamine-like activity. Proteomic analysis closely correlates with toxicological profiles, since the venom of C. s. simus has high amounts of crotoxin and of serine proteinases, whereas the venomof C. s. culminatus presents higher amounts of metalloproteinases and crotamine. This complex pattern of intraspecies venom variation provides valuable information for the diagnosis and clinicalmanagement of envenoming by this species in Mexico, as well as for the preparation of venom pools for the production and quality control of antivenoms. Biological significance This study describes the variation in venomcomposition and activities of the three subspecies of Crotalus simus fromMexico. Results demonstrate that there is a notorious difference in these venoms, particularly regarding the content of the potent neurotoxic phospholipase A2 complex ‘crotoxin’. In addition, other differences were observed regarding myotoxic and coagulant activities, and expression of the myotoxin ‘crotamine’. These findings have implications in, at least, three levels: (a) the adaptive role of variations in venom composition; (b) the possible differences in the clinical manifestations of envenomings by these subspecies in Mexico; and (c) the design of venom mixtures for the preparation of antivenoms effective in the neutralization of the venoms of the three subspecies.Consejo Nacional de Rectores//CONARE/Costa RicaUniversidad de Costa Rica/[741-B2-652]/UCR/Costa RicaConsejo Nacional de Ciencia y Tecnología//CONACyT/MéxicoUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP