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At least 19 recordsLinked to original sources
PubMed2001

Determination of mevalonic acid in human urine as mevalonic acid lactone by gas chromatography-mass spectrometry.

Mevalonic acid in urine is converted to its lactone form by incubation overnight at acidic pH, extracted and analysed by GC-MS. The lower limit of quantitation of 7.5 ng/ml provides adequate sensitivity to measure changes in urinary excretion of MVA following administration of drugs which affect cholesterol synthesis. The assay is linear up to 300 ng/ml and has acceptable precision (<15%) and accuracy (<+/-20%) across the calibration range.

Calibration↗
PubMed1994

Prevention of fluvastatin-induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation.

Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.

Analysis of Variance↗
PubMed1982

Neutrophils are required for the DNA synthetic response of human lymphocytes to mevalonic acid: evidence suggesting that a nonsterol product of mevalonate is involved.

Human peripheral blood lymphocytes, in the presence of human neutrophils, initiate DNA synthesis and cell cycling when exposed to mevalonic acid. The ability of lymphocytes to respond in this manner is a radiosensitive property of cells, whereas the help provided by neutrophils is maintained despite their exposure to x-irradiation. Other organic acid anions, including precursors of mevalonic acid biosynthesis and a variety of products of mevalonate metabolism, fail to initiate DNA synthesis when added to human lymphocytes. Because only the metabolically active R(--) enantiomer of mevalonic acid initiates lymphocyte DNA synthesis, we presume that physiological pathways of mevalonate metabolism are involved. The response to mevalonic acid of ML-236B (compactin)-inhibited lymphocytes is increased, and the threshold concentration of meyalonate at which lymphocyte DNA synthesis first appears is decreased, when the cells are cultured in lipoprotein-containing (as opposed to lipoprotein-depleted) medium. The response to mevalonic acid of lymphocytes cultured in lipoprotein-depleted medium can be enhanced by addition to the cultures of low density lipoprotein but not by addition of high density lipoprotein. Based upon the flux diversion hypothesis of mevalonate metabolism, these observations suggest that a nonsterol product of mevalonate metabolism may be responsible for the initiation of lymphocyte DNA synthesis by mevalonic acid.

Cell Cycle↗
PubMed1990

An improved chemical ionization assay for mevalonic acid.

The determination of mevalonic acid by gas chromatography/mass spectrometry (GC/MS) is complicated by poor extractability and multiple product formation. Reliable quantification down to physiological levels was achieved by isolating mevalonic acid by liquid partition chromatography and quantifying the underivatized lactone by means of ammonia chemical ionization, selected ion monitoring, capillary GC/MS. (2H3)mevalonic acid served as the internal standard. The method appears to be suitable for the study of mevalonic aciduria as well as the evaluation of different therapeutic regimens in patients with hypercholesterolaemia.

Amniotic Fluid↗
PubMed1983

Neutrophil-assisted DNA synthesis by human lymphocytes in response to mevalonic acid; enhancement by cytochalasin B.

Mevalonic acid is capable of initiating DNA synthesis, morphologic transformation, and cell division in cultures of human peripheral blood lymphocytes. Pure populations of lymphocytes respond poorly to mevalonic acid, but their response can be enhanced by peripheral blood neutrophils. Addition of cytochalasin B (0.5-1.0 micrograms/ml), but not cytochalasin A, to mixed neutrophil-lymphocyte cultures enhances the response of lymphocytes to both Con A and mevalonate, but the increment in mevalonate-induced DNA synthesis (+343%) far exceeds the enhancement which cytochalasin B produces in the Con A response (+24%). As a consequence, the DNA synthetic response in mevalonate (10(-2) M) containing cultures averages 39% of the response to an optimal dose of Con A. The cytochalasin B-enhanced response of mixed neutrophil-lymphocyte cultures to mevalonate is abolished by prior X irradiation of the lymphocytes, or their pretreatment with mitomycin C, as well as by the addition of hydroxyurea to the cultures but is not altered by prior X irradiation or mitomycin C pretreatment of the neutrophil helper population. These experiments suggest that the enhancing effect of cytochalasin B in the response of mixed neutrophil-lymphocyte cultures to mevalonic acid results from its ability to potentiate a time-dependent conditioning effect on lymphocytes which neutrophils exert. The conditioning effect of neutrophils cannot be achieved by cell-free neutrophil lysosomal enzymes released by exocytosis, and reactive oxygen species potentially generated by neutrophils are not involved. Attempts to demonstrate the production by neutrophils of a soluble mediator induced by mevalonate in the presence of cytochalasin B were without success. In the presence of cytochalasin B, only the metabolically active R(-) enantiomeric form of mevalonate is capable of initiating DNA synthesis in mixed neutrophil-lymphocyte cultures. The cytochalasin B-potentiated response of mixed neutrophil-lymphocyte cultures to mevalonic acid is preferentially displayed in cultures containing E-rosette-negative, as opposed to E-rosette-positive, lymphocytes. These observations add to the growing knowledge about the relationship between mevalonate metabolism, DNA synthesis, and cell replication.

Cell Cycle↗
PubMed1984

Mevalonic acid induces DNA synthesis in chronic lymphocytic leukemia cells.

Mevalonic acid can stimulate leukemic cells from some patients with B cell chronic lymphocytic leukemia (CLL) to enter the cell cycle in vitro and to synthesize DNA. Unlike normal human peripheral blood lymphocytes, which require the presence of granulocytes for a maximal DNA synthetic response to mevalonic acid, CLL cells do not require a helper cell. Only the physiologically active R(-) enantiomer of mevalonic acid is active in initiating DNA synthesis, and no stimulatory effect is noted after addition of the precursors of mevalonic acid or of its known products. The mitogenic responses to mevalonic acid measured in CLL cells from 35 patients varied widely (range of stimulation indices, 1.2-18.6), but the DNA synthetic response of CLL cells from 9 patients to mevalonic acid exceeded those seen with such common lymphocyte mitogens as concanavalin A, phytohemagglutinin, poke-weed mitogen, or a phorbol ester. The mevalonate-responsive CLL cell was enriched in the E(-), M(+) rosette subpopulation. When CLL cells were incubated in lipoprotein-depleted serum-containing medium, the presence of low density lipoprotein (LDL) cholesterol increased their sensitivity to mevalonic acid transformation, suggesting that a nonsterol product of mevalonic acid metabolism may be involved. Mevalonic acid, which is essential for the growth of cells programmed to divide or stimulated to divide by mitogens, can by itself initiate cell replication in relatively inert G0 phase normal and neoplastic lymphocyte populations.

B-Lymphocytes↗
PubMed1996

Urinary excretion of mevalonic acid as an indicator of cholesterol synthesis.

Urinary excretion of mevalonic acid was investigated as an indicator of cholesterol synthesis. In normolipemic volunteers, excretion of mevalonic acid averaged 3.51 +/- 0.59 (SD) micrograms/kg x day1; (n = 24) and was not different from patients with hypercholesterolemia (3.30 +/- 0.92 micrograms/kg x day1; n = 24). In patients with cerebrotendineous xanthomatosis, the excretion was significantly higher (8.55 +/- 1.92 micrograms/kg x day1; n = 6, P < 0.001) but comparable to volunteers treated with cholestyramine (6.69 +/- 2.6 micrograms/kg x day1; n = 5). A significant correlation was found between 24-h excretion of mevalonic acid and cholesterol synthesis (r = 0.835; n = 35; P < 0.001). The coefficient of variation of excretion of mevalonic acid during 3 consecutive days was small (9.8%; n = 7). However, urinary output of mevalonic acid was significantly higher during the night (164 +/- 14 micrograms/12-h) than during the day (129 +/- 9 micrograms/12-h; n = 11; P < 0.05). In patients treated with simvastatin (40 mg/day) for 6 weeks, the ratio of mevalonic acid to creatinine in a morning urine sample decreased significantly compared to pretreatment values (110 +/- 25 micrograms/g vs. 66 +/- 25 micrograms/g; P < 0.001). Furthermore, the ratio of mevalonic acid to creatinine in a morning urine sample correlated with the ratio from the 24-h collection period (r = 0.714; n = 34; P < 0.001). The results indicate that the analysis of urinary mevalonic acid, either in 24-h collection or in a single morning sample, is an attractive method for evaluation of long and very short term changes of the rates of cholesterol synthesis.

Adult↗
PubMed2000

Urinary excretion and serum concentration of mevalonic acid during acute intake of alcohol.

The influence of 2 different alcoholic beverages containing an equal amount of alcohol (48 g), 1 with mevalonic acid (beer) and 1 without (vodka), on the urinary excretion and serum concentration of mevalonic acid was investigated in 7 healthy subjects. Drinking 1 L of beer at night containing 608 microg/L mevalonic acid more than doubled the urinary excretion of mevalonic acid the following 12 hours, on average from 103 +/- 15 microg/12 h to 211 +/- 17 microg/12 h (P < .001; 18% of the administered dose). Drinking the same amount of alcohol as vodka had no effect, but urinary mevalonic acid output increased slightly the following day (7 AM to 7 PM) after ingestion of both alcoholic beverages. Serum concentrations of mevalonic acid were significantly increased the following morning after ingestion of beer (from 3.22 +/- 0.20 ng/mL to 6.79 +/- 0.58 ng/mL) or vodka (from 3.23 +/- 0.37 ng/mL to 5.36 +/- 0.55 ng/mL, P < .002 for both). An increase in the ratio of lathosterol to cholesterol in serum, another indicator of 3beta-hydroxy-3beta-methylglutaryl coenzyme A reductase activity in the liver, was also observed (+18% and +25%, respectively). After oral administration of [13C2] mevalonic acid at night, 20% +/- 0.7% of the dose was excreted in urine the following 12 hours, and only trace amounts thereafter. No [13C2] mevalonic acid could be detected in serum the following morning. We conclude that the absorption of dietary mevalonic acid and alcohol-induced mevalonic acid synthesis affects the urinary excretion and serum concentration of this cholesterol precursor. Therefore, studies using mevalonic acid as a marker of cholesterol synthesis must be carefully monitored regarding dietary mevalonic acid intake and alcohol consumption.

Adult↗