ians are certainly of endogenous origin. The steroidal bufadienolides appear to be synthesized from cholesterol by the bufonid toads (16). It has been suggested that structurally similar and toxic lucibufagins of fireflies might also be produced by the insect from dietary cholesterol (17). However, toxic cardenolides in monarch butterflies appear to be sequestered from milkweed plants by the larvae (18). The chemical defensive attributes of the highly toxic bufadienolides are due to effects on membrane Na+/K+-ATPase.

The origin of tetrodotoxins in amphibians and higher organisms remains enigmatic. Thus, puffer fish raised in hatcheries do not contain tetrodotoxin (19), and likely biosynthetic precursors are not incorporated into tetrodotoxin with newts (20). Feeding nontoxic puffer fish with tetrodotoxin does not result in sequestration, but feeding toxic ovaries from wild puffer fish does (19). A bacterial origin for tetrodotoxin has been suggested, but such a source fails to explain the fact that one Central American species of toad of the genus Atelopus contains mainly tetrodotoxin; another Central American species contains mainly chiriquitoxin, which is a unique but structurally similar toxin; and yet another contains mainly zetekitoxin, which is another unique, probably structurally related toxin (see ref. 12). Chiriquitoxin, while related in structure to tetrodotoxin, differs in the carbon skeleton (21). The chemical defensive attributes of tetrodotoxin are due to blockade of voltage-dependent sodium channels and hence cessation of neuronal and muscle activity.

The origin of the lipophilic alkaloids in dendrobatid frogs, engendered by the observation that the frogs, which are used by Colombian Indians to poison blow darts, when raised in captivity contain none of the toxic batrachotoxins present in wild-caught frogs (22), remains to be investigated. In contrast, the toxic samandarines from fire salamanders are present in the skin glands of the salamander through many generations of nurture in captivity (G. Habermehl, personal communication). The various lipophilic alkaloids of amphibians all have marked activity on ion channels and hence through such effects would serve effectively as chemical defenses, even though some have relatively low toxicity.

The batrachotoxins were the first class of unique alkaloids to be characterized from skin extracts of frogs of the family Dendrobatidae (see ref. 23 for a review of amphibian alkaloids). Batrachotoxin was detected in only five species of dendrobatid frogs and these frogs were then classified as the monophyletic genus Phyllobates, based in part on the presence of batrachotoxins (24). However, levels of batrachotoxins differ considerably, with the Colombian Phyllobates terribilis containing nearly 1 mg of batrachotoxins per frog, while the somewhat smaller Phyllobates bicolor and Phyllobates aurotaenia, also from the rain forests of the Pacific versant in Colombia, contain 10-fold lower skin levels (8). The two



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