Pharmacological Characterization of Toxins from Death Adder (Acanthophis) Venoms. 

Hodgson, W.C. and Wickramaratna, J.C.

Monash Venom Group, Department of Pharmacology, Monash University, Vic 3800, Australia. 

Death adders (Acanthophis; Elapidae) are found not only in continental Australia, but North throughout the Torres Straight Islands, Papua New Guinea, Irian Jaya and the Indonesian islands of Seram, Halmahera, Obi and Tanimbar. Apart from the venom of the common death adder (A. antarcticus), the majority of death adder venoms, and their components, have not been characterised. We have previously shown that death adder venoms are among the most potent neurotoxic terrestrial snake venoms. Subsequently we have isolated two neurotoxins from death adder venoms. These are: acantoxin IVa from A. sp. Seram (an unnamed species from the island of Seram) venom and acantoxin Va from A. rugosus (Irian Jayan death adder) venom. Acantoxin IVa (MW 6815) is a short-chain neurotoxin that causes pseudo-irreversible antagonism at skeletal muscle nAChR. Acantoxin IVa has a pA2 of 8.36 ± 0.17 (i.e. ~2-fold less potent than the long-chain neurotoxin a-bungarotoxin). With a pKi value of 4.48, acantoxin IVa is ~25,000 times less potent than a-bungarotoxin at a7-type neuronal nAChR. Acantoxin IVa has no activity at ganglionic nAChR, a4b2 subtype neuronal nAChR or cytisine-resistant [³H]-epibatidine binding sites. Acantoxin Va (MW 7991) is a long-chain neurotoxin that causes pseudo-irreversible antagonism at skeletal muscle nAChR. Acantoxin Va has a pA2 of 7.72 ± 0.12 (i.e. ~10-fold less potent than a-bungarotoxin). Acantoxin Va has a pKi value of 7.02 at a7-type neuronal nAChR. Acantoxin Va has no activity at a4b2 subtype neuronal nAChR or cytisine-resistant [³H]-epibatidine binding sites. These are the first two neurotoxins isolated from A. sp Seram and A. rugosus venoms. It has long been thought that death adder venoms are devoid of myotoxic activity. However, rhabdomyolysis has been reported in patients following death adder envenomations in Papua New Guinea. Consequently, we examined A. rugosus venom for myotoxic activity, and isolated the first myotoxin (i.e. acanmyotoxin-1; MW 13811) from a death adder venom. Acanmyotoxin-1 displayed high PLA2 activity (i.e. 153.4 ± 11 mmol/min/mg) and produced inhibition of direct twitches in the chick biventer cervicis nerve-muscle preparation. In addition, morphological changes in skeletal muscle were observed. CSL death adder antivenom or inactivation of PLA2 activity with 4-bromophenacyl bromide prevented this myotoxicity. Death adder venoms remain a largely untapped source of potentially novel toxins.

Correspondence to: wayne.hodgson@med.monash.edu.au