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Biomedical subjects

B Behnke

Publications and source records attributed to B Behnke.

At least 19 recordsLinked to original sources
PubMed2002

Effects of the antirheumatic remedy hox alpha--a new stinging nettle leaf extract--on matrix metalloproteinases in human chondrocytes in vitro.

Inflammatory joint diseases are characterized by enhanced extracellular matrix degradation which is predominantly mediated by cytokine-stimulated upregulation of matrix metalloproteinase (MMP) expression. Besides tumour necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta) produced by articular chondrocytes and synovial macrophages, is the most important cytokine stimulating MMP expression under inflammatory conditions. Blockade of these two cytokines and their downstream effectors are suitable molecular targets of antirheumatic therapy. Hox alpha is a novel stinging nettle (Urtica dioica/Urtica urens) leaf extract used for treatment of rheumatic diseases. The aim of the present study was to clarify the effects of Hox alpha and the monosubstance 13-HOTrE (13-Hydroxyoctadecatrienic acid) on the expression of matrix metalloproteinase-1, -3 and -9 proteins (MMP-1, -3, -9). Human chondrocytes were cultured on collagen type-II-coated petri dishes, exposed to IL-1beta and treated with or without Hox alpha and 13-HOTrE. A close analysis by immunofluorescence microscopy and western blot analysis showed that Hox alpha and 13-HOTrE significantly suppressed IL-1beta-induced expression of matrix metalloproteinase-1, -3 and -9 proteins on the chondrocytes in vitro. The potential of Hox alpha and 13-HOTrE to suppress the expression of matrix metalloproteinases may explain the clinical efficacy of stinging nettle leaf extracts in treatment of rheumatoid arthritis. These results suggest that the monosubstance 13-HOTrE is one of the more active antiinflammatory substances in Hox alpha and that Hox alpha may be a promising remedy for therapy of inflammatory joint diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Bone mineral density in children with primary hyperoxaluria type I.

BACKGROUND: In primary hyperoxaluria type I (PH 1), hepatic overproduction of oxalate leads to its deposition in various organ systems including bone (oxalosis). To evaluate skeletal status non-invasively in PH 1 we measured bone mineral density (BMD). METHODS: Peripheral quantitative computed tomography of the distal radius was performed in 10 children with PH 1 (mean chronological age 9+/-3.1, mean skeletal age 8.3+/-3.0 years): seven were on conservative treatment (CT) including one patient after pre-emptive liver transplantation (PH1-CT) and three were studied with end-stage renal disease on peritoneal dialysis (PH1-ESRD). RESULTS: Mean trabecular bone density (TBD) was significantly increased in PH1-ESRD compared with both age-matched healthy and uraemic controls (65227 vs. 168+/-63 and 256+/-80 mg/cm(3); P<0.002 and P<0.007, respectively), while cortical bone density (CBD) was elevated to a lesser degree (517+/-23 vs. 348+/-81 vs. 385+/-113 mg/cm(3); P<0.02 and P<0.04, respectively). In PH 1, CBD and, even more so, TBD were significantly correlated with serum creatinine (r=0.91 and r=0.96, P<0.0001, respectively) and plasma oxalate levels (r=0.86 and r=0.94, P<0.001 and P<0.0001, respectively). In children with PH 1 and normal glomerular function, both CBD and TBD were comparable with healthy controls. CONCLUSION: These preliminary data suggest that in PH 1 BMD is significantly increased in ESRD, probably due to oxalate disposal. Measurement of BMD may be a valuable and non-invasive tool in determining and monitoring oxalate burden in this disorder.

Bone Density↗
PubMed2000

Fluorescence imaging of frit effects in capillary separations.

The gradient of five dansylated amino acids in a capillary-based separation system commonly used in capillary liquid chromatography (LC) or capillary electrochromatography (CEC) was followed and examined in detail using a detection method based on laser-induced fluorescence imaging. The detection system consisted of an XeCl excimer laser and an image-intensified charge-coupled device (CCD) camera. Fluorescence intensity profiles along the capillary column were displayed and continuously updated on a computer screen. The detector system enabled the separation dynamics in the column to be monitored. The experiments were focused on the course of events, especially at interfaces. The processes occurring at the beginning of the reversed-phase packing material were studied as well as at the transition from stationary phase to the outlet frit and the open tubular area. Striking differences in signal intensity and separation efficiency were revealed depending on where on the column detection was performed. Furthermore, adsorption of the analytes on the frits was observed.

Amino Acids↗
PubMed1999

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.

Animals↗
PubMed1999

Tryptic digest mapping by gradient capillary electrochromatography.

A high performance liquid chromatography (HPLC) system complemented with T-split, capillary detection cell and a high voltage power supply was used for peptide mapping by gradient electrochromatography and nanoliquid chromatography (nano-LC). With capillary columns of 100 microm ID, 6 cm packed with octadecylated 1.5 microm silica particles, the typical analysis time was approximately 10-15 min. The resolution of a tryptic digest of cytochrome c obtained by electrochromatography at 100 kV/m was superior compared to the analysis by nano-LC. Bubble formation caused by Joule heating at currents up to 100 microA was successfully suppressed by using a resistor capillary of 25 microm ID connected to the outlet of the packed column.

Chromatography, Liquid↗
PubMed1999

Enhancing of anti-viral activity against HIV-1 by stimulation of CD8+ T cells with thymic peptides.

HIV-1 can be neutralized by soluble factors produced and secreted by activated CD8+ T cells. Production of such anti-viral CD8 factors (including chemokines) can be induced with IL-2 or phytohaemagglutinin (PHA). In addition to PHA or IL-2, we have co-stimulated CD8+ T cells with PHA/IL-2 and a mixture of thymic peptides (TP) of molecular weights below 10 kD. For the activation, CD8+ T cells were purified from peripheral blood mononuclear cells of HIV-1- individuals and any resultant anti-viral activity was monitored using an HIV-1 neutralization assay. Using HIV-1 isolates highly resistant to chemokine inhibition we detected significantly higher levels of HIV-1 neutralizing activity in CD8+ T cell culture supernatants which had been co-activated with TP. When the TP-induced anti-viral activity was monitored, neutralization of both non-syncytia-inducing (NSI) and syncytia-inducing (SI) patient isolates was enhanced by 38% (NSI, PHA +/- TP), 66% (SI, PHA +/- TP), 28% (NSI, IL-2 +/- TP), and 57% (SI, IL-2 +/- TP) compared with the anti-viral activity present in supernatants from CD8+ T cell cultures stimulated only with PHA or IL-2. Peptide sequence analysis of purified TP showed that the TP mixture predominantly contains peptides with homology to human histone and collagen sequences. Our data demonstrate that CD8+ T cells are additionally activated by a mixture of TP. In this way, the production of HIV-1 neutralizing CD8 factors can be enhanced.

Adjuvants, Immunologic↗
PubMed1999

Antirheumatic effect of IDS 23, a stinging nettle leaf extract, on in vitro expression of T helper cytokines.

OBJECTIVE: Stinging nettle leaf extracts are registered in Germany for adjuvant therapy of rheumatic diseases. In a whole blood culture system the nettle extract IDS 23 (Rheuma-Hek) inhibited lipopolysaccharide stimulated monocyte cytokine expression, indicating an immunomodulating effect. We investigated the immunomodulating effects of IDS 23 on phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC) in vitro. METHODS: Using commercial immunoassays the distinct cytokine patterns of Th1 and Th2 cells were determined. Interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) mRNA expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) with PHA stimulated PBMC. RESULTS: IDS 23 inhibited PHA stimulated production of Th1-specific IL-2 and IFN-gamma in PBMC culture (n = 10) in a dose dependent manner up to 50+/-32% and 77+/-14%, respectively. In contrast, IDS 23 stimulated the secretion of Th2-specific IL-4. The dose dependent inhibiting effect on IL-2 and IFN-gamma expression was also detected with RT-PCR, while the amount of actin-specific mRNA transcript was not modified by IDS 23. CONCLUSION: Our results suggest the effective ingredient of IDS 23 acts by mediating a switch in T helper cell derived cytokine patterns. IDS 23 may inhibit the inflammatory cascade in autoimmune diseases like rheumatoid arthritis.

Antirheumatic Agents↗
PubMed1998

Effects of antihypertensive drugs on cholesterol metabolism of human mononuclear leukocytes and hepatoma cells.

OBJECTIVES: Primary prevention trials of antihypertensive therapy have shown conflicting results on coronary events. Potential interference of antihypertensive agents with cellular lipid metabolism may alter the atherosclerotic risk of individuals. DESIGN AND METHODS: The effects of the calcium antagonist's verapamil, diltiazem, and nifedipine and of the beta-blockers propranolol and metoprolol on low density lipoprotein (LDL) receptor activity, cholesterol esterification rate, oleate incorporation in triglycerides and sterol synthesis were studied in freshly isolated human leukocytes and HEP G2 cells. RESULTS: Up to a concentration of 3-10 mumol/L, verapamil, propranolol, and metoprolol led to an increased cellular content of 125I-LDL by an inhibition of degradation. In mononuclear cells verapamil stimulated accumulation and degradation. No effect on binding was observed. Diltiazem was only stimulatory on 125I-LDL processing in leukocytes. Beta blockers and verapamil significantly reduced the LDL mediated 14C-oleate incorporation in cholesterol esters. In the presence of 25-hydroxycholesterol the esterification was not diminished, which suggests that cholesterolacyltransferase (ACAT) was not affected per se. Whereas all the agents induced the synthesis of lanosterol, metoprolol inhibited cholesterol synthesis. None of the agents had a significant influence on 14C-oleate incorporation in triglycerides, suggesting a specific influence on cholesterol metabolism. CONCLUSIONS: Antihypertensive drugs affect the cholesterol metabolism on a cellular level. Mechanisms are an interference with degradation of LDL and consequent alterations of cholesterol esterification. Using leukocytes as peripheral cells and HEP G2 as a model of human liver, these results may have importance when antihypertensive long-term therapy is conducted for primary or secondary prevention of atherosclerotic complications.

Antihypertensive Agents↗
PubMed1998

Bone alkaline phosphatase in children with chronic renal failure.

BACKGROUND: With the introduction of a new immunoradiometric assay based on two monoclonal antibodies (Tandem-Ostase, Hybritech) the determination of bone alkaline phosphatase (BAP) to evaluate bone metabolism in chronic renal failure has become easier and more valid. SUBJECTS AND METHODS: Using this test we investigated BAP in a total of 90 paediatric patients, 42 (9.2+/-5.5 years) with chronic renal failure on conservative treatment, 22 (9.5+/-5.4 years) under chronic dialysis, and 26 (16.2+/-5.9 years) after renal transplantation, compared to 203 controls (10.1+/-5.7 years). RESULTS: The physiological age dependency found in controls including two peaks during infancy and puberty was distinctly disturbed in chronic renal failure. However, in patients BAP significantly correlated with height velocity rather reflecting the last 6 (r=0.56 P<0.001) than the last 12 months. Although BAP correlated well with total alkaline phosphatase (TAP; r=0.95 P<0.001), a significant correlation with the serum level of the intact parathyroid hormone could only be detected for BAP (r=0.45 P<0.001) but not for TAP (r=0.19 n.s.). Furthermore, BAP positively correlated with trabecular (n=40; r=0.40 P<0.05) and inversely with cortical bone density (n=19; r=-0.58 P<0.01) but no relationship was found with conventional X-ray. CONCLUSION: BAP determined by the new radioimmunoassay seems to represent an additional diagnostic tool to assess growth and bone turnover in paediatric patients with chronic renal failure that is complementary to the information provided by X-ray and total alkaline phosphatase.

Adolescent↗
PubMed1997

Enzyme activities in tissue of human benign prostatic hyperplasia after three months' treatment with the Sabal serrulata extract IDS 89 (Strogen) or placebo.

OBJECTIVE: The mechanism of action of plant extracts used for the medical treatment of human benign prostatic hyperplasia (BPH) is still unknown. In this prospective, randomized, double-blind trial, we investigated the possible influence of the Sabal serrulata extract IDS 89 (Strogen) on epithelial and stromal enzyme activities of BPH tissue. METHODS: 18 patients with BPH were randomly assigned to receive 3 x 2 capsules Strogen uno (320 mg/capsule) (n = 8) or placebo (n = 10) daily for 3 months. The activity (Vmax and Km) of 5 alpha-reductase. 3 alpha-HSORred, 3 beta-HSORred, and creatine kinase was determined in mechanically separated epithelium and stroma of human BPH. RESULTS: The multivariate correlation analysis revealed a positive correlation between therapy and the following enzyme alterations: (1) In epithelium, the substrate affinity of the 5 alpha-reductase decreased slightly (increase of Km value). (2) In stroma, the Vmax value of the 3 alpha-HSORred increased statistically distinctly, leading to a moderate increase of Vmax/Km. (3) In stroma, the Vmax value of the 3 beta-HSORred increased moderately, but not statistically significant. (4) In stroma, the Vmax value of creatine kinase increased significantly, leading to a statistically distinct increase of Vmax/Km. CONCLUSION: This double-blind, placebo-controlled clinical trial with the S. serrulata extract IDS 89 revealed significant biochemical changes at the cellular level of BPH tissue. However, the alterations are merely moderate, their biochemical causes and consequences regarding the pathophysiology of BPH rather uncertain. Therefore, more studies are needed before plant extracts like IDS 89 become valid candidates likewise synthetic substances already used for medical treatment of human BPH.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Effects of the sabal serrulata extract IDS 89 and its subfractions on 5 alpha-reductase activity in human benign prostatic hyperplasia.

Extract from fruit of Sabal serrulata are used in the treatment of human benign prostate hyperplasia (BPH). Therefore, it is of interest whether this phytopharmacon has any influence on the androgen metabolism in the human prostate. It was found that the extract IDS 89 of Sabal serrulata inhibited dose dependently 5 alpha-reductase activity in the epithelium and stroma of human BPH, the mean inhibition being 29% and 45%, respectively. This inhibitory effect is mainly due to the saponifiable subfraction of IDS 89 showing a mean 5 alpha-reductase inhibition of 39% and 38% in epithelium and stroma, respectively. The inhibition was dose dependent and noncompetitive. At a testosterone concentration of 580 nM as substrate for 5 alpha-reductase, the main fatty acids of the extract IDS 89 gave rise to a percentual enzyme inhibition in the epithelium and stroma as follows: 51% and 42% (lauric acid), 5% and 0% (oleic acid), 43% and 34% (myristic acid), 2% and 0% (palmitic acid), respectively. The inhibitory effect of lauric acid was noncompetitive and dose dependent up to a concentration of 0.2 nM, the maximal inhibition in the epithelium and stroma being 52% and 45%, respectively. The nonsaponifiable subfraction, consisting mainly of phytosterols, showed a mean inhibition of 5 alpha-reductase in the epithelium and stroma of 15% and 10%, respectively. Finally, the hydrophilic subfraction, containing carbohydrates, amino acids, and polysaccharides, showed no inhibitory effect. The present in vitro studies suggest that the Sabal serrulata extract IDS 89 has an inhibitory effect on 5 alpha-reductase in the epithelium and stroma of human BPH. This inhibition is mainly due to the fatty acids of the saponifiable subfraction.

Cholestenone 5 alpha-Reductase↗
PubMed1996

In vitro inhibition of testicular delta 5-3 beta-hydroxysteroid dehydrogenase and prostatic 5 alpha-reductase activities in rats and humans by strogen forte extract.

Clinical findings indicate that Strogen forte (a standardized extract of the plant Sabalis serrulata) can be use successfully in the medical treatment of benign prostatic hyperplasia. The aim of the present study was to investigate the possible inhibitory effects of the Strogen forte extract on rat and human testicular delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) and prostatic 5 alpha-reductase (5 alpha-R). Strogen forte proved to be a direct inhibitor of medium effectivity, with similar IC50 values for rat testicular delta 5-3 beta-HSD (400 +/- 23 micrograms/ml) and human testicular delta 5-3 beta-HSD (212 +/- 8.6 micrograms/ml). 5 alpha-R activities were analysed by in vitro incubation of rat and human prostatic tissue homogenates with 14C-labelled testosterone as substrate in KRPG-DTT medium (pH = 7.4) with NADPH coenzyme, in air, at 37 degrees C, in the presence of Strogen forte extract. The results clearly demonstrate that Strogen forte is a potent inhibitor of prostatic 5 alpha-R, with IC50 values of 385 +/- 35.6 micrograms/ml for rat and 245 +/- 64.6 micrograms/ml for human prostatic 5 alpha-R. The present study has revealed that this plant extract inhibits not only prostatic 5 alpha-R, but also testicular delta 5-3 beta-HSD.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum urticae dioicae foliorum.

An extract of Urtica dioica folium (IDS 23, Rheuma-Hek), monographed positively for adjuvant therapy of rheumatic diseases and with known effects in partial inhibition of prostaglandin and leukotriene synthesis in vitro, was investigated with respect to effects of the extract on the lipopolysaccharide (LPS) stimulated secretion of proinflammatory cytokines in human whole blood of healthy volunteers. In the assay system used, LPS stimulated human whole blood showed a straight increase of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion reaching maximum concentrations within 24 h following a plateau and slight decrease up to 65 h, respectively. The concentrations of these cytokines was strongly positively correlated with the number of monocytes/macrophages of each volunteer. TNF-alpha and IL-1 beta concentration after LPS stimulation was significantly reduced by simultaneously given IDS 23 in a strictly dose dependent manner. At time 24 h these cytokine concentrations were reduced by 50.8% and 99.7%, respectively, using the highest test IDS 23 assay concentration of 5 mg/ml (p < 0.001). After 65 h the corresponding inhibition was 38.9% and 99.9%, respectively (p < 0.001). On the other hand IDS 23 showed no inhibition but stimulated IL-6 secretion in absence of LPS alone. Simultaneously given LPS and IDS 23 resulted in no further increase. In contrast to described effects on arachidonic acid cascade in vitro, tested Urtica dioica phenol carbon acid derivates and flavonoides such as caffeic malic acid, caffeic acid, chlorogenic acid, quercetin and rutin did not influence LPS stimulated TNF-alpha, IL-1 beta and IL-6 secretion in tested concentrations up to 5 x 10(-5) mol/l. These further findings on the pharmacological mechanism of action of Urticae dioica folia may explain the positive effects of this extract in the treatment of rheumatic diseases.

Adult↗
PubMed1996

[Anti-inflammatory effect of Urtica dioica folia extract in comparison to caffeic malic acid].

Urtica dioica extract is a traditionary used adjuvant therapeutic in rheumatoid arthritis. The antiphlogistic effects of the urtica dioica folia extract IDS 23 (Extractum Urticae dioicae foliorum) and the main phenolic ingredient caffeic malic acid were tested concerning the inhibitory potential on biosynthesis of arachidonic acid metabolites in vitro. The caffeic malic acid was isolated from Urtica folia extract using gel exclusion- and high performance liquid chromatography and identified by mass spectroscopy and nuclear magnetic resonance. Concerning the 5-lipoxygenase products IDS 23 showed a partial inhibitory effect. The isolated phenolic acid inhibited the synthesis of the leukotriene B4 in a concentration dependent manner. The concentration for halfmaximal inhibition (IC50) was 83 microns/ml in the used assay. IDS 23 showed a strong concentration dependent inhibition of the synthesis of cyclooxygenase derived reactions. The IC50 were 92 micrograms/ml for IDS 23 and 38 micrograms/ml for the caffeic malic acid. Calculating the content in IDS 23 the caffeic malic acid is a possible but not the only active ingredient of the plant extract in the tested assay systems. It is demonstrated that the phenolic component showed a different enzymatic target compared with IDS 23. The antiphlogistic effects observed in vitro may give an explanation for the pharmacological and clinical effects of IDS 23 in therapie of rheumatoid diseases.

Animals↗
PubMed1996

Bone mineral density in pediatric patients after renal transplantation.

To evaluate the natural history of bone mineral density after successful renal transplantation (TPL) modulated by therapeutic strategies in pediatric patients we have studied peripheral and partially proximal quantitative computed radius tomography (XCT) differentiating between trabecular (TBD), cortical (CBD) and total bone density (BD) cross-sectionally in a group of 24 subjects (mean age 17.1 +/- 7.0 y, mean Scr 1.66 +/- 0.89), 66.1 months (5-260) post transplant and compared the results with 12 controls. After TPL median TBD was elevated (182.5 vs. 155.5 mg/cm3) whereas the opposite was true for CBD (361.8 vs. 437.8 mg/cm3). The physiologic age dependency of BD had got lost after TPL but could be reassumed by the measurement of proximal CBD. TBD correlated with the cumulative calcitriol dosage (r = 0.60, p < 0.05), bone alkaline phosphatase (r = 0.55, p < 0.01), the Ca x P product (r = 0.43, p < 0.05) and inversely with the time after TPL (r = -0.45, p < 0.05), but no significant correlation could be detected with the cumulative steroid dose. It was found to be higher in calcitriol treated than in vitamin D3 treated patients. Proximal CBD was inversely correlated with bone alkaline phosphatase (r = -0.71, p < 0.01) and intact PTH (r = -0.59, p < 0.05). In conclusion CBD in kidney grafted pediatric patients seems to be more or less reduced by secondary hyperparathyroidism whereas the increase of TBD appears to be induced by anticipated calcitriol treatment under dialysis regimen and gradually normalizes after TPL.

Adolescent↗
PubMed1996

[The in vitro induction of monocyte chemotactic protein-1 and interleukin-8 in whole human blood by low molecular weight thymus peptides].

Thymic peptides show immunoreconstitutive und tumor suppressive effects. They are used in oncology to improve the immunological status of patients. Chemokines are able to activate immune cells and inhibit tumor growth. In this study it was proved whether low molecular thymic peptides are able to increase the secretion of the chemokines monocyte chemotactic protein-1 (MCP-1), interleukin-8 (IL-8), macrophage inflammatory protein-1 alpha (MIP-1 alpha) and macrophage inflammatory protein-1 beta (MIP-1 beta) as well as the cytokine tumor necrosis factor-alpha (TNF-alpha) which is not related to chemokines using cell cultures of human whole blood. The thymic peptides induced a significant (p < 0.05) elevated secretion of MCP-1 and IL-8 whereas for MIP-1 alpha, MIP-1 beta and TNF-alpha no significant chances were seen. MCP-1 and IL-8 showed divergent dose-dependent effects and a different time kinetic of their secretion. The MCP-1 concentration correlated positively with the count of monocytes in whole blood of the volunteers while the IL-8 concentration in dependence with the incubation time correlated positively with the count of granulocytes or monocytes of the volunteers. The results indicate an activation of monocytes and/or granulocytes by low molecular thymic peptides followed by selective elevated secretion of MCP-1 and IL-8.

Adult↗
PubMed1994

Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes.

There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular cholesterol metabolism in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 20 h in a lipid-free medium resulted in an increase in the rate of cholesterol synthesis from [14C]acetate and the high affinity accumulation and degradation of [125I]labeled low density lipoprotein (LDL). Addition of melatonin in increasing concentrations to the incubation medium at zero time inhibited cholesterol synthesis and the specific accumulation and degradation of [125I]labeled LDL; at a concentration of 100 microM, the inhibitions were 38%, 42%, and 48%, respectively. Similar results were obtained using [14C]mevalonate as precursor. Fatty acid synthesis was not altered under these conditions. In contrast to cholesterol, the synthesis of the first cyclic compound lanosterol was not affected by the pineal hormone. These results implicate that melatonin inhibits this pathway between lanosterol and cholesterol. The action of melatonin on LDL receptor activity appeared to be mediated by a decrease in the number of LDL receptors and not by a change in binding affinity. Pharmacological characterization of the potential melatonin receptor site using several analogs like tryptamine, 5-hydroxytryptamine,N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine, and 6-chloromelatonin indicated that the 5-methoxy group is indispensible for the hormone action on cholesterol synthesis. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.

5-Methoxytryptamine↗