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Biomedical subjects

J D Finkelstein

Publications and source records attributed to J D Finkelstein.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Persistent hypermethioninaemia with dominant inheritance.

A clinically benign form of persistent hypermethioninaemia with probable dominant inheritance was demonstrated in three generations of one family. Plasma methionine concentrations were between 87 and 475 mumol/L (normal mean 26 mumol/L; range 10-40 mumol/L); urinary methionine and homocystine concentrations were normal. Plasma homocystine, cystathionine, cystine and tyrosine were virtually normal. The concentrations in serum and urine of metabolites formed by the methionine transamination pathway were normal or moderately elevated. Methionine loading of two affected family members revealed a diminished ability to catabolize methionine, but the activities of methionine adenosyltransferase and cystathionine beta-synthase were not decreased in fibroblasts from four affected family members. Fibroblast methylenetetrahydrofolate reductase activity and its inhibition by S-adenosylmethionine were also normal, indicating normal regulation of N5-methyltetrahydrofolate-dependent homocysteine remethylation. Serum folate concentrations were not increased. The findings in this family differ from those previously described for known defects of methionine degradation. Since the hepatic and fibroblast isoenzymes of methionine adenosyltransferase differ in their genetic control, this family's biochemical findings appear consistent with a mutation in the structural gene for the hepatic methionine adenosyltransferase isoenzyme.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Methionine metabolism in mammals. The methionine-sparing effect of cystine.

Cystine can replace approximately 70% of the dietary requirement for methionine. We used standard enzyme assays, determinations of the hepatic concentrations of metabolites and an in vitro system which simulates the regulatory site formed by the enzymes which utilize homocysteine in this study of the mechanism for this adaptation. A significant alteration in the pattern of hepatic homocysteine metabolism occurs following the substitution of cystine for methionine. The major change is a marked reduction in the synthesis of cystathionine. Decreases in both the level of cystathionine synthase and in the concentration of adenosyl-methionine, a positive effector of the enzyme, explain this finding. Despite significant increases in the hepatic levels of betaine-homocysteine methyltransferase and methyltetrahydrofolate-homocysteine methyltransferase, flow through these reactions remains relatively constant. The betaine enzyme may be essential for efficient methionine conservation. In the absence of choline, cystine cannot replace methionine in an adequate diet limited in the latter amino acid.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1988

Effect of nicotinamide on methionine metabolism in rat liver.

To test the response to increased utilization of methyl groups, we administered large dosages of nicotinamide to rats fed an adequate diet that contained limited amounts of methionine and choline. During the 4 d after the injection, we observed several significant effects on the hepatic concentrations of the enzymes and metabolites of methionine metabolism. Methionine and S-adenosylmethionine remained at control levels; the concentrations of S-adenosylhomocysteine exceeded the control values from 4 to 16 h; and the levels of serine and betaine were lower after 16 h. Treatment with nicotinamide resulted in higher hepatic levels of methionine adenosyltransferase (after 4 h) and cystathionine synthase (after 16 h). These data indicate that increases in both homocysteine methylation and S-adenosylmethionine synthesis may be components of the response to excessive methyl group consumption. An increased synthesis of cystathionine would provide for the removal of S-adenosylhomocysteine (and homocysteine) derived from the adenosylmethionine-dependent methylation of nicotinamide.

Animals↗
PubMed1988

Transsulfuration in an adult with hepatic methionine adenosyltransferase deficiency.

We investigated sulfur and methyl group metabolism in a 31-yr-old man with partial hepatic methionine adenosyltransferase (MAT) deficiency. The patient's cultured fibroblasts and erythrocytes had normal MAT activity. Hepatic S-adenosylmethionine (SAM) was slightly decreased. This clinically normal individual lives with a 20-30-fold elevation of plasma methionine (0.72 mM). He excretes in his urine methionine and L-methionine-d-sulfoxide (2.7 mmol/d), a mixed disulfide of methanethiol and a thiol bound to an unidentified group X, which we abbreviate CH3S-SX (2.1 mmol/d), and smaller quantities of 4-methylthio-2-oxobutyrate and 3-methylthiopropionate. His breath contains 17-fold normal concentrations of dimethylsulfide. He converts only 6-7 mmol/d of methionine sulfur to inorganic sulfate. This abnormally low rate is due not to a decreased flux through the primarily defective enzyme, MAT, since SAM is produced at an essentially normal rate of 18 mmol/d, but rather to a rate of homocysteine methylation which is abnormally high in the face of the very elevated methionine concentrations demonstrated in this patient. These findings support the view that SAM (which is marginally low in this patient) is an important regulator that helps to determine the partitioning of homocysteine between degradation via cystathionine and conservation by reformation of methionine. In addition, these studies demonstrate that the methionine transamination pathway operates in the presence of an elevated body load of that amino acid in human beings, but is not sufficient to maintain methionine levels in a normal range.

Adult↗
PubMed1987

Hepatic methionine adenosyltransferase deficiency in a 31-year-old man.

A 31-year-old man with hepatic methionine adenosyltransferase (MAT) deficiency was evaluated for an odd odor to his breath. He had no other symptoms. Plasma methionine was 716 microM (normal, 15-40 microM), and plasma methionine-oxidation products were 460 microM (normal, 0). Hepatic MAT activity was 28% of normal. Unlike the control human enzyme, the patient's residual MAT activity was not stimulated by 10% dimethylsulfoxide and the velocity was not increased by high substrate concentration; at 1.0 mM methionine, the patient's MAT activity was only 7% of normal. These biochemical findings are consistent with a deficiency of the high-Km isoenzyme of MAT. Despite this enzyme deficiency, liver histology and clinical tests of hepatic and other organ function were normal. The patient, who is 25 years older than the oldest reported individual with MAT deficiency, provides evidence that partial MAT deficiency is a benign disorder and that chronic hypermethioninemia (less than 1 mM) is not by itself detrimental to health.

Adult↗
PubMed1986

Methionine metabolism in mammals. Adaptation to methionine excess.

We conducted a systematic evaluation of the effects of increasing levels of dietary methionine on the metabolites and enzymes of methionine metabolism in rat liver. Significant decreases in hepatic concentrations of betaine and serine occurred when the dietary methionine was raised from 0.3 to 1.0%. We observed increased concentrations of S-adenosylhomocysteine in livers of rats fed 1.5% methionine and of S-adenosylmethionine and methionine only when the diet contained 3.0% methionine. Methionine supplementation resulted in decreased hepatic levels of methyltetrahydrofolate-homocysteine methyltransferase and increased levels of methionine adenosyltransferase, betaine-homocysteine methyltransferase, and cystathionine synthase. We used these data to simulate the regulatory locus formed by the enzymes which metabolize homocysteine in livers of rats fed 0.3% methionine, 1.5% methionine, and 3.0% methionine. In comparison to the model for the 0.3% methionine diet group, the model for the 3.0% methionine animals demonstrates a 12-fold increase in the synthesis of cystathionine, a 150% increase in flow through the betaine reaction, and a 550% increase in total metabolism of homocysteine. The concentrations of substrates and other metabolites are significant determinants of this apparent adaptation.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1986

Reduced acetylation of procainamide by para-aminobenzoic acid.

Acetylation is the major route of metabolism of many drugs including the antiarrhythmic agent procainamide. Coadministration of para-aminobenzoic acid was observed to decrease the biotransformation of procainamide to N-acetylprocainamide in a patient with rapid acetylation kinetics. In view of the distinct antiarrhythmic and toxic properties of procainamide and N-acetylprocainamide, the observed drug interference may have great clinical relevance in long-term oral antiarrhythmic therapy and in instances where other drugs converge for acetylation.

4-Aminobenzoic Acid↗
PubMed1986

Effect of dietary cystine on methionine metabolism in rat liver.

Cystine supplementation of adequate diets resulted in significantly higher hepatic levels of betaine-homocysteine methyltransferase. Other changes occurred but were a function of the basal diet. When the latter contained 0.25% methionine + 0.5% cystine, the additional cystine caused a markedly lower hepatic cystathionine synthase activity and lower levels of both adenosylmethionine and serine. The metabolic effect of these changes may be enhanced methionine retention and diminished transsulfuration.

Animals↗
PubMed1984

Methionine metabolism in mammals. Distribution of homocysteine between competing pathways.

Using an in vitro system which contained enzymes, substrates, and other reactants at concentrations which approximated the in vivo conditions in rat liver, we measured the simultaneous product formation by three enzymes which utilize homocysteine. In the control system, 5-methyltetrahydrofolate homocysteine methyltransferase, betaine homocysteine methyltransferase, and cystathionine beta-synthase accounted for 27, 27, and 46%, respectively, of the homocysteine consumed. Subsequent studies demonstrated that the adaptation from a high protein diet to a low protein diet is achieved by a significant increase in betaine homocysteine methyltransferase, and 83% reduction in cystathionine synthase, and a total decrease of 55% in the consumption of homocysteine. S-Adenosylmethionine, by activating cystathionine synthase, contributes significantly to the regulation of the pathway.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1984

Inactivation of betaine-homocysteine methyltransferase by adenosylmethionine and adenosylethionine.

Preincubation of betaine-homocysteine methyltransferase, prepared from rat liver, with either S-adenosylmethionine or S-adenosylethionine results in a marked loss of enzyme activity. Gel filtration did not restore activity. However both S-adenosylhomocysteine and L-homocysteine, when added to the preincubation medium, inhibited the inactivation of betaine-homocysteine methyltransferase.

Adenosine↗
PubMed1983

Regulation of hepatic betaine-homocysteine methyltransferase by dietary betaine.

The level of betaine-homocysteine methyltransferase increases in the livers of rats fed diets supplemented with betaine or choline. The increase occurs within 3 days following the change in diet. When we administered betaine by intraperitoneal injection to rats fed choline-free diets, we observed a similar increase within 24 hours. Since betaine-homocysteine methyltransferase catalyzes a reaction which is essential for the catabolism of betaine, these changes provide a means for adaptation to excessive levels of dietary choline and betaine.

Animals↗
PubMed1982

Methionine metabolism in mammals: concentration of metabolites in rat tissues.

We have evaluated factors which regulate the content of methionine, adenosylmethionine, adenosylhomocysteine, cystine, cysteine and acid-soluble thiols in rat tissues. In liver the concentration of methionine appears relatively insensitive to changes in dietary protein intake. In contrast the hepatic levels of adenosylmethionine, adenosylhomocysteine, cystine, cysteine and soluble thiols increased with augmented dietary protein. The ratio of adenosylmethionine: adenosylhomocysteine approximated 6.0 in livers, brains, kidneys and skeletal muscles from rats fed the stock diet. Independent variation in the concentrations of these two metabolites did occur. However, the ratios in livers of animals maintained on diets with varying casein content equaled or exceeded a value of 5.0. We conclude that the maintenance of the concentration of methionine is the primary result of the various homeostatic mechanisms. In addition, most previous reports have overestimated the tissue content of adenosylhomocysteine.

Amino Acids, Sulfur↗