Einfluss einkettiger Lipide auf das Monooxygenasesystem der Humanleber
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Cytochrome P4503A4 is the most important P450 enzyme for drug metabolism in humans because it participates in the metabolism of the majority of drugs with known metabolic pathways. The effect of single-chain phospholipids on CYP3A4 was studied using in vitro preparations of recombinant human CYP3A4 and recombinant human NADPH-Cytochrome P450 reductase incorporated into a binary vesicular phospholipid system of dilauroyl-phosphatidyl-choline and phosphatidyl-serine. Enzyme activity was measured with a direct fluorometric assay using dibenzylfluorescein and the resulting fluorescent product fluorescein. CYP3A4 was inhibited by the myristic acid derivative myristoylcarnitine, IC(50) 25 microM; palmitoyl-L-carnitine, IC(50) 6 microM; monoacyl-sn-glycero-3phospho-[1-D-myoinositol] (L-a-lysophosphatidylinositol), IC(50) 6 microM; L-a-lysophosphatidylcholine (monoacyl-sn-glycero-3-phosphocholine), IC(50) 2.7 microM; oleic acid (cis-9-octadecenoic acid), IC(50) 3 microM, arachidonic acid (5,8,11,14-eicosatetraenoic acid), IC(50) 6 microM; phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), IC(50) 5 microM. Oleic acid and L-a-lysophosphatidylcholine show competitive inhibition and dissociation coefficients of 1.49 and 2.79 microM, respectively. CYP3A4 was activated by the lauric acid derivative lauroylcarnitine, AC(50) 20 microM; 2-monopalmitoylglycerol, AC(50) 7.5 microM; 2-monooleoylglycerol (2-monoolein), AC(50) 1.9 microM. Whereas AC(50) values depend on the solubility of each lipid, IC(50) values depend on the substrate dibenzylfluorescein. Unsaturated lipids inhibit more than saturated lipids and the inhibitory effect of saturated lipids decreases with the number of carbon atoms. In vitro findings are extrapolated to the likely in vivo situation and an inhibitory effect is suggested for all alkylphosphocholines. It is concluded that modulation of CYP3A4 by single-chain lipids occurs in the micromolar range.
Subject HeadingsAlkylphosphocholine [GND]
Cytochrome P 450 [GND]