At what stage in metazoan evolution did leukotriene generation first appear?—key insights from cartilaginous fish

Abstract

Leukotriene (LT) B 4 is a key player in inflammatory responses in mammals. During the generation of this derivative of arachidonic acid, the unstable product of 5-lipoxygenase, termed LTA 4, is converted to LTB 4 by LTA 4 hydrolase. Invertebrates do not generate LTs yet all vertebrates from bony fish onwards synthesize this compound. As cartilaginous fish are the most primitive living jawed vertebrates, we investigated if the leukocytes from such a fish, the Thornback ray ( Raja clavata) could generate LTB 4. Supernatants from ionophore-challenged leukocytes generated the 5-lipoxygenase products, 6- trans-LTB 4 and 6- trans-12- epi-LTB 4 but were unable to synthesize LTB 4. To determine if these cells contained an active LTA 4 hydrolase, LTA 4 was incubated with lysates from ray leukocytes. Such preparations did not contain any demonstrable LTA 4 hydrolase activity. Our findings imply at the stage of cartilaginous fish evolution over 350 million years ago that the evolution of an active LTA 4 hydrolase had yet to occur.