Leukotriene B4 (LTB4), a biologically active metabolite derived from arachidonic acid by the 5-lipoxygenase cascade, is inactivated by cytochrome P-450-dependent ω-hydroxylation followed by second oxidation into a ω- carboxyl group. In many tissues, this second step is mediated by alcohol dehydrogenase. Isolated rat hepatocytes metabolized LTB4 in the presence of ethanol and ethoxyresorufin into substantial quantities of 3-hydroxy-LTB4 as determined by mass spectrometry. The absolute configuration of this metabolite was found to be greater than 98% 3(S)-hydroxy-LTB4 by comparison to synthetic standards. Investigation of the pharmacologic properties of the 3(S)- and 3(R)-hydroxy-LTB4 revealed that both caused a significant increase in intracellular free calcium in human neutrophils at 1 μM. Both enantiomers also induced thromboxane A2 release from the isolated guinea pig lung in a dose-dependent manner. This activity was fully blocked by a specific LTB4 receptor antagonist, LY223982, with an IC50 of 0.21 μM for LTB4. These results suggested that activation of the LTB4 receptor does not involve significant recognition of the carbon atoms close to the carboxyl moiety of LTB4. The failure of the hepatocyte to metabolically inactivate LTB4 in the presence of ethanol may be of importance to humans, particularly because the bioactive metabolite 3(S)-hydroxy-LTB4 was further metabolized by human neutrophils significantly more slowly than LTB4.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1994|
ASJC Scopus subject areas
- Molecular Medicine