Kamlesh Chauhan

20-Hydroxyeicosatetraenoic acid is excreted as a glucuronide conjugate in human urine

20-hydroxyeicosatetraenoic acid, a major renal P-450 metabolite of arachidonic acid, has been quantified in human urine using capillary gas chromatography/electron capture negative ion chemical ionization mass spectrometry. The urinary excretion of 20-hydroxyeicosatetraenoic acid was in the low pg/ml range. However, treatment of urine with beta-glucuronidase resulted in a 13- to 28-fold increase in its concentration. This suggests 20-hydroxyeicosatetraenoic acid differs from other eicosanoids in that it is excreted primarily as a glucuronide conjugate.

Oxidation and keto reduction of 12-hydroxy-5,8,10,14-eicosatetraenoic acids in bovine corneal epithelial microsomes

The R and S enantiomers of 12-hydroxyeicosatetraenoic acid (12-HETE) exhibit different biological activities. Although they appear to be produced by different enzymatic pathways, cytochrome P-450 monooxygenase and lipoxygenase, respectively, they display similar metabolism in both corneal epithelium and neutrophils. In corneal epithelial microsomes, both enantiomers are subject to oxidation and keto reduction reactions to form the dihydro metabolite, 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), via a keto intermediate. The apparent Km for the formation of 12-HETrE was 17.9 and 20 microM for 12(R)-HETE and 12(S)-HETE, respectively, and the apparent Vmax of the reaction was 17.4 and 8.2 pmol/mg per min, respectively. Chiral analysis of the dihydro metabolite demonstrated a product enantiospecificity. Arachidonic acid, 12(R)-HETE, 12(S)-HETE and the intermediate of this reaction, 12-oxo-ETrE, were metabolized predominantly to 12(R)-HETrE in a ratio [12(R)-HETrE: 12(S)-HETrE] of 7.3:1, 4.3:1, 1.5:1 and 2.3:1, respectively. 12(R)-HETrE is a potent vasodilator, chemotactic and angiogenic factor whose synthesis is induced in inflamed tissues; 12(S)HETrE is devoid of these properties. 12(R)-HETE, derived from NADPH-dependent cytochrome P-450 monooxygenases, and 12(S)-HETE, derived from 12-lipoxygenase, may both play an important role in regulating the inflammatory response by serving as substrates for the local synthesis of 12(R)-HETrE.

Eicosanoid biosynthesis: Differential inhibition of cytochrome P450 epoxygenase and ω-hydroxylase

Abstract Biphenyl 4 and vinyldibromide 8 were prepared on a multigram scale and shown to be comparatively specific arachidonic acid epoxygenase and ω-hydroxylase inhibitors, respectively, in rat kidney microsomal fractions.

Total synthesis of the ethanol inducible, proinflammatory autacoid 3(S)-hydroxy-leukotriene B4 (3-OH-LTB4) and analogues

Abstract 3(S)-Hydroxy-Leukotriene B 4 ( 1a ), its 3(R)-epimer 1b , and a 14,15-acetylenic analogue were efficiently prepared via chelation-controlled reduction of ketone 12 , obtained by acetylide addition to chiral β-hydroxylactones 7/9 .

Vasoactive eicosanoids: Synthesis of 12,20-dihydroxyeicosa-5(Z),8(Z),10(E),14(Z)-tetraenoic acid via a novel chiral bis-lactol

Abstract The type IIB eicosanoids, 12(R),20- and 12(S),20-dihydroxyeicosatetraenoic acid (DiHETE), were conveniently synthesized utilizing a carbohydrate-derived bis-lactol as a differentiated 4-hydroxyhex-2(E)-enedial chiron. 12(S),20-DiHETE, but not the 12(R)-isomer, induced vasodilation in precontracted canine arteries.

Angiogenic factors: syntheses of 12(R)- and 12(S)-hydroxyeicosa-5(Z),8(Z),14(Z)-trienoic acid and their 14,15-dehydro analogs

Abstract The title autacoids and acetylenic analogs were conveniently prepared from 2-deoxy- D -ribose via Barton deoxygenation, cuprate coupling, and Wittig homologation. 12(R)-HETrE, but not the 12(S)-isomer, significantly stimulated microvessel endothelial cell proliferation and proto-oncogene mRNA levels at sub-nano to picomolar concentrations. A high affinity binding site for 12(R)-HETrE was detected on microvessle endothelial cells.

3(S)-hydroxy-leukotriene B4 is a potent granulocyte chemotaxin in the guinea pig dermis.

Leukotriene B 4 (LTB4), a product of arachidonic acid metabolism by the 5-1ipoxygenase pathway, is a potent granulocyte activator proposed as an important mediator A. of inflammatory and immune responses. Catabolic processes inactivate LTB4, however, low levels of ethanol (2-10mM) interfere with normal B-oxidation of LTB4 ~ o.2oby hepatocytes resulting in the accumulation of a novel =~ metabolite, 3(S)-hydroxy-LTB 4 [3(S)-OH-LTB4] [1, 2]. This metabolite may well be the long-sought, ethanol-inducible ~ 0.15 chemotactic agent responsible for the recruitment of neutrophils into liver parenchyma and the subsequent ~ 0.10 tissue damage therein [3]. We assessed the ability of 3(S)OH-LTB4 to recruit granulocytes into the guinea pig skin by the dermal content of the neutrophil marker enzyme, ~ 0.0s myeloperoxidase (MPO), and by histology. SC-53228 {(+ )(S)-7-[3-[2-(cyclopropylmethyl)-3-methoxy-4 [(methylami.= no)carbonyl] phenoxy[proproxy]-3,4-dihydro-8-propyl~ o.oo 2H-l-benzopyran-2-propanoic acid} is a potent, orally active, second generation LTB~ receptor antagonist and B. we investigated its ability to antagonize the chemotactic activity of 3(S)-OH-LTB4 [4, 5].

Vic-Diol chirons : enantiospecific synthesis of 11,12- and 14,15-dihydroxyeicosatrienoic acids

Abstract A differentiated, six-carbon vicinal -diol chiron was prepared from D -glucurono-6,3-lactone and exploited in the asymmetric synthesis of the erythro/threo -isomers of the title eicosanoids.