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F J Trijbels

Publications and source records attributed to F J Trijbels.

At least 55 records · Page 3Linked to original sources
PubMed1995

Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia.

Thermolability of 5,10-methylenetetrahydrofolate reductase (MTHFR) was examined as a possible cause of mild hyperhomocysteinemia in patients with premature vascular disease. Control subjects and vascular patients with mild hyperhomocysteinemia and with normohomocysteinemia were studied. The mean (+/- SD) specific MTHFR activity in lymphocytes of 22 control subjects was 15.6 (+/- 4.7) nmol CH2O/mg protein/h (range: 9.1-26.6), and the residual activity (+/- SD) after heat inactivation for 5 min at 46 degrees C was 55.3 (+/- 12.0)% (range: 35.9-78.3). By measurement of MTHFR activity, two distinct subgroups of hyperhomocysteinemic patients became evident. One group (n = 11) had thermolabile MTHFR with a mean (+/- SD) specific activity of 8.7 (+/- 2.1) nmol CH2O/mg protein/h (range: 5.5-12.7) and a residual activity, after heat inactivation, ranging from 0% to 33%. The other group (n = 28) had normal specific activity (+/- SD) of 21.5 (+/- 7.2) nmol CH2O/mg protein/h (range: 10.0-39.0) and a normal residual activity (+/- SD) of 53.8 (+/- 9.2)% (range: 33.1-71.5) after heat inactivation. The mean (+/- SD) specific activity of 29 normohomocysteinemic patients was 20.7 (+/- 6.5) nmol CH2O/mg protein/h (range: 9.4-33.8), and the mean (+/- SD) residual activity after heat inactivation was 58.2 (+/- 10.2)% (range: 43.0-82.0). Thus, in 28% of the hyperhomocysteinemic patients with premature vascular disease, abnormal homocysteine metabolism could be attributed to thermolabile MTHFR.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1994

Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts.

6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR.

Adenosine Triphosphate↗
PubMed1994

Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos.

Mild hyperhomocysteinemia is frequently observed in mothers who gave birth to a child with a neural tube defect (NTD). In a previous study we showed L-homocysteine was embryotoxic to gestational day 10 (GD10) rat embryos in culture, however, no NTDs were observed. We therefore investigated the effect of L-homocysteine on the development of neural plate stage (GD9.5) rat embryos. Other objectives of this study were investigation into whether the embryotoxicity of L-homocysteine could be attenuated by compounds related to its metabolism and clarification of the mechanism of L-homocysteine embryotoxicity. In GD9.5 rat embryos L-homocysteine was not toxic at 1- and 2-mM concentrations. Rather at these concentrations it promoted development of the rat embryos in serum that without supplementation caused NTDs in the embryos. L-Methionine had the same preventive effect at even lower concentrations, but folinic acid (1 mM) did not improve embryonic development. N5-Methyltetrahydrofolate (5-CH3-THF) (100 microM), L-serine (6 mM), and L-methionine (6 and 12 mM) attenuated the embryotoxicity of L-homocysteine (6 mM) in GD10 rat embryos. Vitamin B12 (10 microM) completely abolished the embryotoxicity of L-homocysteine, which was shown to be mediated by catalysis of the spontaneous oxidation of L-homocysteine to the less toxic L-homocystine. In GD11 rat embryos, both L- and D-homocysteine were readily taken up when added to the culture (3 mM) and increased embryonic S-adenosylhomocysteine (SAH) levels 14- and 3-fold, respectively. This difference was shown to be caused by the stereospecific preference of SAH hydrolase. We propose the basis for L-homocysteine embryotoxicity is an inhibition of transmethylation reactions by increased embryonic SAH levels.

Adenosylhomocysteinase↗
PubMed1994

Maternal hyperhomocysteinemia: a risk factor for neural-tube defects?

The maternal vitamin status, especially of folate, is involved in the pathogenesis of neural-tube defects (NTDs). Maternal folate administration can prevent these malformations. The precise metabolic mechanism of the beneficial effect of folate is unclear. In this study we focus on homocysteine accumulation, which may derive from abnormalities of metabolism of folate, vitamin B12, and vitamin B6. We studied nonpregnant women, 41 of whom had given birth to infants with NTDs and 50 control women who previously had normal offspring. The determinations included the plasma total homocysteine both in the fasting state and 6 hours after the ingestion of a methionine load. In addition, we measured the fasting blood levels of folate, vitamin B12, and vitamin B6. The mean values for both basal homocysteine and homocysteine following a methionine load were significantly increased in the group of women who previously had infants with NTDs. In nine of these subjects and two controls, the values after methionine ingestion exceeded the mean control by more than 2 standard deviations. Cystathionine synthase levels in skin fibroblasts derived from these methionine-intolerant women were within the normal range. Our findings suggest a disorder in the remethylation of homocysteine to methionine due to an acquired (ie, nutritional) or inherited derangement of folate or vitamin B12 metabolism. Increased homocysteine levels can be normalized by administration of vitamin B6 or folate. Therefore, we suggest that the prevention of NTDs by periconceptional folate administration may effectively correct a mild to moderate hyperhomocysteinemia.

Adult↗
PubMed1994

Treatment of mild hyperhomocysteinemia in vascular disease patients.

Mild hyperhomocysteinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocysteinemia. Thirty-three percent of patients with peripheral and 20% of patients with cerebral occlusive arterial disease were identified with mild hyperhomocysteinemia (14% of the men, 34% of the premenopausal women, and 26% of the postmenopausal women). Mildly hyperhomocysteinemic patients were administered vitamin B6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with nonnormalized homocysteine concentrations were further treated with vitamin B6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B6 treatment normalized the afterload homocysteine concentration in 56% of the treated patients (71% of the men, 45% of the premenopausal women, and 88% of the postmenopausal women). Further treatment resulted in a normalization of homocysteine levels in 95% of the remaining cases. Thus, mild hyperhomocysteinemia, which is frequently encountered in patients with premature arteriosclerotic disease, can be reduced to normal in virtually all cases by safe and simple treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism.

Adult↗
PubMed1994

Inhibition of IMP dehydrogenase by mycophenolic acid in Molt F4 human malignant lymphoblasts.

The effects of inhibition of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide de novo synthesis, on cell growth, cell viability, endogenous nucleotide concentrations and concentrations of extracellular nucleosides and bases were studied in Molt F4 human malignant lymphoblasts. Mycophenolic acid (MPA) was used as a specific inhibitor of the enzyme activity. IMPDH activity was maximally inhibited with 0.5 microM MPA. After a 2 h exposure of the cells to 0.5 microM MPA, guanine nucleotides were depleted to approximately 50% of control values, whereas 5-phosphoribosyl-1-pyrophosphate levels increased to approximately 200%. Under these conditions, cytotoxicity became obvious after 24 h. Depletion of guanine nucleotides and cytotoxicity were prevented by addition of guanosine to MPA treatment. Daily supplements of guanosine were required to prevent MPA cytotoxicity during the entire incubation period of 72 h. We conclude that depletion of guanine nucleotides, induced by treatment with MPA, induces a severe and rapid cytotoxicity in Molt F4 cells.

Cell Division↗
PubMed1993

Reversal of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside cytotoxicity by amidoimidazole carboxamide ribonucleoside in Molt F4 human malignant T-lymphoblasts.

Cytotoxicity of 6-mercaptopurine (6MP) and 6-methylmercaptopurine ribonucleoside (Me-MPR) was studied in Molt F4 human malignant lymphoblasts. Both drugs are converted into methylthioIMP (Me-tIMP), which inhibits purine de novo synthesis. Addition of amidoimidazole carboxamide ribonucleoside (AICAR) circumvented inhibition of purine de novo synthesis, and thus partly prevented 6MP and Me-MPR cytotoxicity. Purine nucleotides, and especially adenine nucleotides, were recovered by addition of AICAR. Under these conditions, Me-tIMP formation decreased. The results of this study indicate that formation of Me-tIMP may be important for 6MP cytotoxicity in Molt F4 cells. These data suggest that depletion of adenine nucleotides is the main cause for Me-tIMP cytotoxicity.

Adenine Nucleotides↗
PubMed1993

The importance of methylthio-IMP for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity in Molt F4 human malignant T-lymphoblasts.

The importance of methyl-thioIMP (Me-tIMP) formation for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity was studied in Molt F4 cells. Cytotoxicity of Me-MPR is caused by Me-tIMP formation with concomitant inhibition of purine de novo synthesis. Inhibition of purine de novo synthesis resulted in decreased purine nucleotide levels and enhanced 5-phosphoribosyl-1-pyrophosphate (PRPP) levels, with concurrent increased pyrimidine nucleotide levels. The Me-tIMP concentration increased proportionally with the concentration of Me-MPR. High Me-tIMP concentration also caused inhibition of PRPP synthesis. Maximal accumulation of PRPP thus occurred at low Me-MPR concentrations. As little as 0.2 microM Me-MPR resulted already after 2 h in maximal inhibition of formation of adenine and guanine nucleotides, caused by inhibition of purine de novo synthesis by Me-tIMP. Under these circumstances increased intracellular PRPP concentrations could be demonstrated, resulting in increased levels of pyrimidine nucleotides. So, in Molt F4 cells, formation of Me-tIMP from Me-MPR results in cytotoxicity by inhibition of purine de novo synthesis.

Cell Division↗
PubMed1993

A biochemical basis for synergism of 6-mercaptopurine and mycophenolic acid in Molt F4, a human malignant T-lymphoblastic cell line.

6-Mercaptopurine (6MP) cytotoxicity was studied in Molt F4 cells, a T-cell acute lymphoblastic leukemia (ALL) cell line. The effects on cytotoxicity were concentration-dependent. Measurements of intracellular thionucleotide intermediates of 6MP demonstrated a rapid rise of thio-IMP (tIMP) levels, and subsequently a rapid decrease. Thio-GMP (tGMP) and methyl-thio-IMP (Me-tIMP) appeared later in time, and persisted longer. Mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase (IMPDH), was used to inhibit the conversion of tIMP into tGMP, thereby decreasing the incorporation of 6MP into DNA. A synergistic effect on cell viability and cell growth was observed when cells were treated with a combination of 2 microM 6MP and 0.5 microM MPA. Also, intracellular Me-tIMP increased 5 times with the combination. Based on the increase of Me-tIMP concentration and the observed synergism between 6MP and MPA, we conclude that methylation of tIMP into Me-tIMP is an important alternative route for 6MP cytotoxicity.

Cytotoxins↗
PubMed1993

Study on the presence of homocysteine in ovarian follicular fluid.

OBJECTIVE: To study the presence of homocysteine, methionine and the vitamins folate, B12, and B6 in human ovarian follicular fluid (FF). DESIGN: Measurement of homocysteine, methionine, folate, and vitamins B12 and B6 in ovarian FF and blood. SETTING: Academic Department of Obstetrics and Gynecology at St. Radboud Hospital, Nijmegen, The Netherlands. PARTICIPANTS: Fourteen healthy women undergoing an IVF program. RESULTS: Detectable amounts of homocysteine and methionine were found in FF. Homocysteine concentrations were similar to those in serum. Methionine concentrations proved to be slightly but significantly lower than in corresponding serum samples. Concentrations of vitamins B12 and B6 were significantly lower in FF than in serum, whereas folate concentrations were not significantly different. A statistically significant correlation between corresponding serum and FF concentrations of homocysteine, folate, and vitamin B12 could be established. CONCLUSIONS: These data support the hypothesis that the ovum might be exposed to high homocysteine or low methionine concentrations, or both, and a lack of vitamins, which might be important in fertilization and early embryogenesis.

Adult↗
PubMed1993

Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss.

OBJECTIVE: To establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss. DESIGN: In a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test. SETTING: Gynecologic outpatient department of university hospital. PATIENTS: One-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected. INTERVENTIONS: Blood samples were collected just before and 6 hours after oral methionine administration to determine plasma total homocysteine concentrations. MAIN OUTCOME MEASURE: Plasma total homocysteine concentrations 6 hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6 hours exceeding the 97.5 percentile level of the controls. RESULTS: Hyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively). CONCLUSION: Hyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.

Abortion, Habitual↗
PubMed1992

Effects of sub-50 oral contraceptives on homocysteine metabolism: a preliminary study.

The influence of a monophasic sub-50 oral contraceptive (OC), Marvelon, on fasting total homocysteine levels was investigated in OC users and controls. Homocysteine levels in serum of OC users were significantly higher (P less than .01) than in controls during the low-hormonal phase of the cycles and comparable with levels determined in heterozygotes for homocystinuria. Blood levels of pyridoxal phosphate (PLP) were significantly lower (P less than .05) in OC users both in the low and high hormonal phase. However, there were no significant differences in the levels of homocysteine nor in folate and vitamin B12 between both groups in the high-hormonal phase. In contrast to the control group, the homocysteine levels in OC users in the high-hormonal phase of the cycle were significantly decreased compared with those on a low-hormonal day (P less than .05). These data suggest that cyclically recurrent periods of hyperhomocysteinemia do occur during sub-50 OC use in normal women and might be considered a predisposition to the occurrence of vascular complications.

Adult↗
PubMed1989

Reference values for amino acids in cerebrospinal fluid of children determined using ion-exchange chromatography with fluorimetric detection.

One thousand specimens of CSF were collected from subjects ranging in age from newborn to 18 yr, who were undergoing a diagnostic lumbar puncture. Sixty-two samples were judged retrospectively as being suitable for calculating reference age-related values. The analyses were performed by an amino acid analyser using ion-exchange chromatography with fluorimetric detection giving a tenfold increase in sensitivity, thereby enhancing the diagnostic capabilities. As many as 36 known compounds could be detected, additionally 10 we could not identify. In children older than 3 yr nine of the identified compounds showed age-dependency. We found 22 amino acids to be significantly higher in infants younger than 1 yr, with only gamma-aminobutyric acid being significantly lower in infants. Alpha-aminoadipic acid showed a sex difference, being slightly higher in girls.

Adolescent↗
PubMed1988

Reference values for nucleosides and nucleobases in cerebrospinal fluid of children.

Disturbances in the metabolism of purines and pyrimidines in neurologically affected patients can be reflected by aberrant concentrations of nucleosides and nucleobases in cerebrospinal fluid (CSF). However, normal values, especially for children at different ages, are lacking. We collected 1000 specimens of CSF from subjects ranging in age from newborn to 18 years, who were undergoing a diagnostic lumbar puncture for several clinical indications. Of these, 78 samples could be used retrospectively as a reference according to our criteria. The analyses were performed with a modified HPLC procedure. None of the substances shows age-dependency except uridine and uric acid. Uridine increases with age, and uric acid increases with age in boys older than 12 years.

Adolescent↗
PubMed1985

Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.

Premature arteriosclerosis and thromboembolic events are well-known complications of homozygous homocystinuria due to cystathionine synthase deficiency. It is unknown whether heterozygosity for homocystinuria predisposes to premature vascular disease. We explored the frequency of excessive homocysteine accumulation after standardized methionine loading in 75 patients presenting with clinical signs of ischemic disease before the age of 50:25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. In seven patients in each of the first two groups but in none of the patients in the third group, heterozygosity for homocystinuria was established on the basis of pathological homocysteinemia after methionine loading and cystathionine synthase deficiency in skin fibroblast cultures. Because the frequency of heterozygosity for homocystinuria in the normal population is 1 in 70 at the most, we conclude that this condition predisposes to the development of premature occlusive arterial disease, causing intermittent claudication, renovascular hypertension, and ischemic cerebrovascular disease.

Adult↗
PubMed1985

Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts.

Previous data on tentative identification of the carrier state for homocystinuria due to cystathionine synthase deficiency using methionine loading or measurement of cystathionine synthase activity in tissue extracts are conflicting. We studied the results of standardized oral methionine loading in 20 obligate heterozygotes and compared them with those of determination of cystathionine synthase activity in cultured fibroblasts. Special attention was devoted to our recently reported observation on the small but striking differences in methionine metabolism between healthy pre- and postmenopausal women and men. Fasting and after load peak levels of methionine in serum did not discriminate the carriers from the control subjects. The mean fasting level of total homocysteine was only significantly higher in the group of premenopausal heterozygotes than in the corresponding control group. Nevertheless, the individual values overlapped with the normal range in 4 of 12 premenopausal heterozygotes. After loading peak levels of total homocysteine in 18 out of the 20 obligate heterozygotes exceeded the upper limit of the ranges in the three control groups. Thus, this parameter discriminated 90% of the obligate carriers. Measurement of cystathionine synthase activity in cultured fibroblasts from a skin biopsy identified the obligate heterozygotes to a similar degree (85%). No significant correlation between the measurements of cystathionine synthase activity and the after load peak levels of total homocysteine in the individual heterozygotes was established. Combination of both methionine loading and determination of cystathionine synthase activity in cultured fibroblasts identified all of these carriers.

Adolescent↗