Nomenclature of lipoxins and related compounds derived from arachidonic acid and eicosapentaenoic acid

Abstract

Oxygenated derivatives of arachidonic acid and eicosapentaenoic acid with contain conjugated tetraene structures and are non-cyclized C20 carboxylic acids were first isolated and characterized from human and porcine leukocytes (Serhan, C.N. et al, 1984, Biochem. Biophys. Res. Commun. 118, 943–949; Wong, P.Y.-K., et al, 1985, Biochem. Biophys. Res. Commun. 126, 765–775). The trivial names lipoxins and lipoxanes have been introduced for compounds belonging to each of these series. Here, we propose that tetraene-containing compounds derived from arachidonic acid be denoted as lipoxins (LX) of the four series (i.e. lipoxin A4 or LXA4 and lipoxin B4 or LXB4) and those derived from elicosapentaenoic be termed lipoxins of the five series (i.e. lipoxin A5 or LXA5 and lipoxin B5 or LXB5).Human leukocytes can transform either 15(S)-hydroperoxy-5,8,11-cis-13-trans-eicosatetraenoic acid; 15(S)-HPETE, or 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid; 15(S)-HETE, to a series of compounds that contain oxygen substituents and four conjugated double bonds (1–4). Following isolation, the basic structures of two main biologically-derived compounds of this series were elucidated by physical methods as well as by chemical degradation and shown to be 5,6,15L-trihydroxy-7,9,11,13-eicosatetraenoic acid and 5D,14,15-trihydroxy-6,8,10,12-eicostetraenoic acid (1,2). In several bioassay systems these materials evole selective adn stereospecific responses which differ from those observed with leukotrienes (reviewed in Ref. 5–7). Since these compounds were new structures and arose by interaction(s) between lipoxygenase pathways, the trivial name lipoxins (LX; lipoxygenase interaction products) was proposed for this series and the bioactive compounds of this series were termed lipoxin A (LXA) and lipoxin B (LXB) (2).Studies with isotopic oxygen (18O2) and intact human leukocytes revealed that lipoxin A, lipoxin B, and their isomers each carried an 18O atom of carbon 5 and that the oxygen substituents at carbon 6 of LXA as well as its isomers and carbon 14 of lipoxin B and its isomers were not derived exclusively from molecular oxygen (3,4,8). Such findings along with the results of alcohol trapping experiments provide evidence for the involvement of a 5(6)-epoxytetraene intermediate in the formation of these compounds (9). The complete stereochemistry of lipoxin A, lipoxin B, and their isomers (the geometry of the double bonds and chirality of the alcohol groups at carbon 6 and carbon 14, respectively) were established utilizing materials prepared by total synthesis (3,4). Biologically derived lipoxin B proved to be 5(S), 14(R), 15(S)-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid and its two naturally occuring isomers are 5(S), 14(R), 15(S)-trihydroxy-6,8,10,12-trans-eicosatetraenoic acid (8-trans-LXB) and 5(S), 14(S), 15(S)-trihydroxy-6,8,10,12-trans-eico-satetraenoic acid (14(S)-8-trans-LXB). Lipoxin A was shown to be 5(S), 6(R), 15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid, and its isomers are 5(S),6(S),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (6(S)-LXA), 5(S),6(R),15(S)-trihydroxy-7,9,11,- 13-trans-eicosatetraenoic acid (11-trans-LXA) and 5(S0,6(S),15(S)-trihydroxy-7,9,13-trans-eicosatetraenoic acid (6(S)-11-trans-LXA). We propose that the trivial names of tetraene-containing compounds derived from arachidonic acid carry the subscript four to denote the 4-series and that structurally distinct members of this series be distinguished by the capital letters A, B, and so forth (e.g. LXA4, LXB4) (See Fig. 1).Like arachidonic acid, eicosapentaenoic acid can be transformed by cyclo-oxygenase to form products of the 3-series, (i.e., thromboxane A3 and PGI3) which may contribute to the cardiovascular effects of eicosapentaenoic acid (10). In addition, eicosapentaenoic acid is a substrate for the 5-lipoxygenase and can be transformed to leukotrienes of the 5-series (11). With this connection, it has been shown that tetrane-containing trihydroxypentaene derivatives of eicosapentaenoic acid can be isolated following incubation of 15(S)-hydroperoxyeicosapentaenoic acid with porcine leukocytes. The trivial name lipoxenes was introduced for compounds of this series (12). Since the eicosapentaenoic acid derived produces are structurally similar to lipoxins of the 4-series we propose that 5,6,15-trihydroxy-7,9,11,13,17-eicosapentaenoic acid and 5,14,15- trihydroxy-6,8,10,12,17-eicosapentaenoic acid and their related isomers be denoted as lipoxin A5 and lipoxin B5 (LXA5, LXB5), respectively.