The skin of frogs and toads is an ambulant pharmacopoeia with hundreds of structurally different biologically active substances identified in the past few decades. This arsenal has the double role of fending off bacteria and fungal pathogens that otherwise would thrive on the soft and humid skin and of defending the animal from larger predators. The "poison frogs" of the family Dendrobatidae—native to the rainforests of South and Central America—have evolved the ability to store in their skin the poisonous lipophilic alkaloids they ingest feeding on ants and other arthropods and to secrete them when challenged. It had been assumed that the sequestered poisons were simply shuttled to the skin, but in the September 1 PNAS, John W. Daly and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases show that these amphibians actively metabolize the alkaloids into more poisonous compounds (PNAS, DOI:10.1073/pnas.1834430100, September 1, 2003).

Daly et al. determined the relative efficiency of uptake of two of the most common classes of alkaloids found in skin of dendrobatid frogs, decahydroquinolines (DHQs) of ant origin and pumiliotoxins (PTXs) from unidentified arthropod sources. They raised poison frogs of the genera Dendrobates, Epipedobates, and Phyllobates in aquaria, feeding them with termites and fruit flies dusted with DHQ iso-223F and PTX (+)-251, and then analyzed the skin extracts by gas chromatography–mass spectrometry. Researchers were surprised to find that while DHQ iso-223F was, as expected, sequestered unchanged in the skin of all frogs, in the Dendrobates species tested, the majority of dietary PTX (+)-251 was instead stereoselectively hydroxylated to give the allopumiliotoxin aPTX (+)-267A, probably through the action of a enantioselective pumiliotoxin 7-hydroxylase, and stored as such in the skin. This finding provides the first evidence that at least some dendrobatid frogs possess the enzymatic machinery needed to metabolize dietary alkaloids. In addition, the authors also observed that the modified alkaloid is at least five times more lethal to mice than the PTXs initially fed to the frogs.

"The evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs," conclude the authors.