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Summary The effect of 9 different pteridines on fatty acid incorporation into phospholipids as well as on cholesterol and phospholipid content was compared in vitro using rat liver homogenate, Krebs-Ringer phosphate buffer containing 0.3 % albumin (pH=7.4), fatty acid mixture and glycerol. D-neopterin (5-30 pmol/g) induced an increase of saturated, a decrease of unsaturated fatty acids incorporation into phospholipids and elevated the cholesterol content in samples. The phospholipid amount in samples remained unchanged. Sepiapterin, 7,8-dihydrobiopterin, 5,6,7,8-tetrahydrobiopterin, biopterin, monapterin and 7,8-dihydroneopterin addition to samples induced an inverse relationship: a decrease of saturated, an increase of unsaturated fatty acid, especially arachidonic acid, incorporation into phospholipids and the decrease of cholesterol content in samples. The phospholipid amount in samples remained unchanged or increased. Lipid metabolism was not altered after addition of xanthopterin and isoxanthopterin to samples. It was suggested that neopterin decreased membrane fluidity, prevented cell cycle, induced cell dystrophy and apoptosis, and promoted the cholesterol precipitation while tetrahydrobiopterin, its precursors, biopterin, monapterin and dihydroneopterin increased membrane fluidity, stimulated cell cycle, prevented cholesterol precipitation. The data point to a potential role of increased neopterin concentrations in vivo to support atherosclerosis development and progression whereas the other pteridines may have a protective effect. Moreover, these pteridines can also promote cell transformation.

Blood serum neopterin, high sensitivity C-reactive protein (hsCRP), total homocysteine, pyridoxal-5-phosphatc ( P-5-P) and total phospholipid concentrations have been examined in 30 healthy individuals as well as in patients with coronary artery disease (CAD) verified by coronary angiography (43 patients with 1-artery disease, 24 patients with 2-or 3-artery disease, 17 patients with restenosis) before percutaneous transluminal coronary angioplasty. We have observed increased mean concentrations of neopterin, hsCRP and homocysteine as well as decreased mean concentration of P-5-P and phospholipids in all groups of CAD patients. The positive correlation between neopterin and hsCRP in all CAD patients (r = 0.536; Ρ <0.01 ) as well as an increased frequency of these indices above the upper limit of normal during the course of CAD (30.1 % in eases with 1-artery disease, 54.2% of cases in 2-or 3-artery disease, 76.5% of cases in restenosis) allow to conclude that inflammation has a pivotal role in the progression of CAD. In restenosis the determination ot neopterin was of more significance than the determination of hsCRP. The combination of a mild increase of neopterin and homocysteine concentrations points to the worst prognosis of CAD, both after percutaneous transluminal coronary angioplasty and coronary bypass, restenosis was most liekly to appear. Mild increase of homocysteine concentration in patients with CAD docts not only indicate possible thickening of arterial wall and narrowing of lumen but also to impaired trans-sulfuration and remethylation pathways of homocysteine metabolism as well as to delayed methylation processes in the organism. A decrease of serum P-5-P concentration, which in all groups of CAD patiens reached about 50% as compared with healthy individuals, points to impairment of all metabolic processes, which require the biologically active form of vitamin B6 for their action. The decrease of mean serum phospholipid concentration in all groups of CAD patients may indicate both, impaired phospholipid biosynthesis due to delayed processes of methylation in the organism and increased loss of phosphatidylcholine necessary for transportation of oxidised low density lipoproteins into macrophages. Therefore the determination of serum phospholipid concentration and phosphatidylcholine concentration, especially, has the same significance in the course of CAD as the determination of total cholesterol, high and low density lipoprotein cholesterol widely used at present.

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Summary Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH = 7.4) containing 0.3% albumin, fatty acid mixture and glyceroL The addition of L-kynurenine (4 nmol/g wet weight), D-eryhro-neopterin (5 and 30 pmol/g wet weight) and noradrenaline (4 nmol/g wet weight) to incubation medium induced an increase of saturated (palmitic acid) and decrease of poly-unsaturated (linoleic and arachidonic acid) fatty acids incorporation into phospholipids. The increase of saturated fatty acids incorporation into phospholipids was more pronounced after addition of neopterin and noradrenaline to the incubation medium while the decrease of linoleic and arachidonic acid synthesis was stimulated most with kynurenine. Moreover, kynurenine stimulated whereas neopterin depressed the oleic acid incorporation into phospholipids. These changes of fatty acid incorporation into phospholipids were followed by increase of cholesterol content in samples containing kynurenine, neopterin or noradrenalin. In contrast, phospholipid content decreased in samples containing kynurenine or noradrenalin, hut was not altered by supplementation of neopterin. Since the addition of kynurenine and neopterin to incubation medium for isolated fog heart resulted in an increased noradrenaline and decreased pyridoxal-5-phosphate content in the tissue, we also added pyridoxal-5-phosphate (4 nmol/g wet weight) to incubation medium for phospholipid biosynthesis. No change of the fatty acid incorporation into phospholipids as welI as the content of phospholipids and cholesterol in samples was observed.

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Impairment of lipid metabolism due to excess metabolite accumulation induced by pyridoxal-5-phosphate (P-5-P)-deficiency andlor stimulated immune system has been studied and interpreted. Decreased amounts of phospholipids as well as deviations in phospholipid classes and fatty acid composition of phospholipids have been demonstrated due to kynurenine accumulation in the blood of P-5-P-deficient cardiovascular patients and white rats as well as in cardiovascular patients with activated immune system identified by an increased neopterin concentration in the blood (dilated cardiomyopathy) . The addition of P-5-P to the incubation medium for phospholipid biosynthesis in vitro did not change fatty acid incorporation into phospholipids, whereas it normalised fatty acid incorporation into phospholipids in liYer homogenates recei,·ed from P-5-P-deficient rats: 'Ine addition of kynurenine, neopterin and noradrenalin (accumulated m isolated heart tissue after addition of kynurenine and neopterin to incubation medium for isolated heart) to incubation medium for phospholipid biosynthesis in vitro induced an increase of saturated and a decrease of polyunsaturated fatty acid incorporation into phospholipids. These changes in fatty acid incorporation into phospholipids were followed by increased cholesterol concentrations in samples and an increased cholesterol/phospholipid ratio. Our results suggest that these changes in lipids are characteristic for decreased membrane fluidity, depressed cell cycle and lowered possibility of phospholipids to keep cholesterol in solution. P-5-P-deficiency is also accompanied with excess accumulation of homocysteine in the blood. The addition of L-homocysteine to the incubation medium for phospholipid biosynthesis in vitro was followed by inverse changes in fatty acid incorporation into phospholipids when compared with kynurenine , neopterin and noradrenalin. L-homocysteine induced a decrease of saturated and an increase of polyunsaturated fatty acid incorporation into phospholipids. The cholesterol concentration decreased in samples and the cholesterol/phospholipid ratio decreased, too . These findings suggest that changes in lipids induced by L-homocysteine are characteristic for increased membrane fluidity and stimulated cell cycle. In this study, we have observed a similar effect to L-homocysteine effect when L-homocysteine, L-tryptophan and 5,6,7,8-tetrahydrobiopterin were added to the incubation medium for phospholipid biosynthesis in vitro. The comparison of our results with data from the literature allows to suggest that excess metabolite accumulation due to activated formation and inactivated catabolism of it plays a significant role in quantitative and qualitative changes of lipids, especially phospholipids, and therefore participates in the regulation of membrane fluidity, cell cycle of normal and malignant cells as well as in keeping cholesterol in the state of solution.