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J. Biol. Chem., Vol. 263, Issue 17, 7996-8002, 06, 1988
RJ Soberman, JP Sutyak, RT Okita, DF Wendelborn, LJ Roberts 2d and KF Austen
Microsomes of human polymorphonuclear leukocytes (PMN) in the presence of
100 microM NADPH converted 0.6 microM leukotriene B4 (LTB4) to 20-OH- LTB4
(retention time = 18.0 min) and to two additional compounds designated I
(retention time = 16.8 min) and II (retention time = 9.6 min) as analyzed
by reverse-phase high performance liquid chromatography (HPLC). Compounds I
and II were also formed from the reaction of 1.0 microM 20-OH-LTB4, PMN
microsomes, and 100 microM NADPH; the identity of compound II was confirmed
as 20-COOH-LTB4 by gas chromatography-mass spectrometry. Equine alcohol
dehydrogenase in the presence of 100 microM NAD+ in 0.2 M glycine buffer
(pH 10.0) converted 20-OH-LTB4 to 20-aldehyde (CHO) LTB4, which coeluted
with compound I on reverse-phase HPLC. In the presence of 100 microM NADH
in 50 mM potassium phosphate buffer (pH 6.5), equine alcohol dehydrogenase
reduced both 20-CHO-LTB4 and compound I to 20-OH-LTB4, indicating the
identity of compound I as 20-CHO-LTB4. Gas chromatography-mass spectrometry
of trideuterated O-methyl-oxime trimethylsilyl ether methyl ester
derivative of 3H-labeled compound I definitively established compound I as
20-CHO-LTB4. Addition of immune IgG to cytochrome P-450 reductase or 1.0 mM
SKF-525A completely inhibited the formation of 20-CHO-LTB4 from 20-OH-LTB4,
indicating that the reaction was catalyzed by a cytochrome P-450. LTB5 (3.0
microM), a known substrate for cytochrome P-450LTB and a competitive
inhibitor of LTB4 omega-oxidation, completely inhibited the omega-oxidation
of 1.5 microM 20-OH-LTB4 to 20-CHO-LTB4, indicating that the cytochrome
P-450 was P- 450LTB. Conversion of 1.0 microM 20-CHO-LTB4 to 20-COOH-LTB4
by PMN microsomes was also dependent on NADPH and inhibited by antibody to
cytochrome P-450 reductase, 1.0 mM SKF-525A, or 5.0 microM LTB5, indicating
that this reaction was also catalyzed by cytochrome P- 450LTB. These
results identify the novel metabolite 20-CHO-LTB4 and indicate that
cytochrome P-450LTB catalyzes three sequential omega- oxidations of LTB4
leading to the formation of 20-COOH-LTB4 via 20-OH- LTB4 and 20-CHO-LTB4
intermediates.
The identification and formation of 20-aldehyde leukotriene B4
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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