Biomedical subjects
Publications and source records attributed to S H Zeisel.
Malnutrition is the primary biologic insult in most cases of failure to thrive. A transactional model of infant development provides a framework for understanding the psychosocial context in which such malnutrition occurs. Each child who fails to thrive should receive a multidisciplinary evaluation to address the diagnostic and therapeutic implications of nutritional, medical, psychosocial, and developmental factors contributing to growth failure.
Nitrosodimethylamine (NDMA) is a potent carcinogen in a wide variety of animal species. In experimental animals, dimethylamine and nitrite, precursors of NDMA, are found in gastric fluid where the acidic conditions are suitable for formation of nitrosamines. In this study we measured the concentrations of mono-, di- and trimethylamine (MMA, DMA and TMA) in gastric fluid from humans, rats, dogs and ferrets, as well as in saliva, blood and urine from humans. Human gastric fluid contained 3.7 +/- 0.4 (SEM) nmol/ml MMA, 12.6 +/- 1.4 nmol/ml DMA and 2.0 +/- 0.4 nmol/ml TMA. MMA, DMA and TMA concentrations in human gastric fluid were similar to those present in human saliva and blood, but were much lower than those present in human urine. The concentrations of these amines in human gastric fluid were lower than those measured in gastric fluid from experimental animals. When we added sodium nitrite to human gastric fluid, NDMA was formed. We have shown that DMA is normally present in human gastric fluid, and that it can be nitrosated to form NDMA.
The effects of end-stage liver disease and orthotopic liver transplantation on components that modulate cholesterol esterification in plasma were assessed. In comparison with healthy controls, patients with end-stage liver disease had significantly decreased concentrations of lecithin-cholesterol acyltransferase mass, apolipoprotein A-1, total phospholipids, and both total and esterified cholesterol. Elevated phosphatidylcholine and reduced lysophosphatidylcholine fractions indicated impairment of cholesterol esterification by lecithin-cholesterol acyltransferase. Constituent fatty acids of the patients' phospholipids and cholesterol esters manifested increased saturation and a concomitant reduction of polyunsaturated fatty acids, indicative of impaired hepatic elongation and desaturation of essential fatty acids. By the third month after hepatic replacement, the plasma concentrations of total cholesterol, phospholipids, lecithin-cholesterol acyltransferase, and apolipoprotein A-1 were comparable to those of the healthy subjects. Despite the improvement in cholesterol esterification and the rapid normalization of the enzyme and cofactor involved in this process, the percentage of phosphatidylcholine remained significantly higher and the percentages of lysophosphatidylcholine and esterified cholesterol remained significantly lower than in the healthy subjects at 6 mo. Phospholipid and cholesterol ester fatty acid patterns attained normalcy by the sixth month after transplant. We conclude that hepatic transplantation effectively restores cholesterol and essential fatty acid metabolism in patients with end-stage liver disease.
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75Se-labeled selenite was administered to fasting rats by orogastric intubation (1.5-3000 micrograms/kg body wt). Urine was collected and characterized for total radioactivity as well as for radiolabeled trimethylselenonium (TMSe). At lower doses of selenite (up to 500 micrograms/kg body wt), 30% of the administered dose was excreted. At higher doses of selenite, fractional urine excretion decreased as a function of the dose. The observed decrease in fractional urine excretion was not caused by changes in the absorption of the administered radiolabel. There was a direct relationship between the amount of the administered dose of selenite (up to 1500 micrograms/kg body wt) and the proportion of urinary [75Se] excreted as TMSe. Pretreatment with seleno compounds (10 or 100 micrograms Se/kg body wt as selenite, or selenomethionine) for 35 d before a challenge dose of [75Se]selenite did not influence the excretion of total [75Se] or of [75Se]TMSe in urine. Ingestion of a choline-deficient diet, which should deplete the availability of methyl groups, did not have any effect on excretion of total [75Se] or of [75Se]TMSe in urine after a challenge dose of [75Se]selenite (500 micrograms/kg body wt). The data presented here permit the following conclusions: 1) Production of TMSe is dose dependent, 2) production of TMSe from a single acute dose does not depend on the history of selenium intake and 3) rats fed a methyl-deficient diet are able to eliminate Se via formation of TMSe.
Choline is an essential nutrient for some mammals; it is used for membrane and neurotransmitter synthesis. We analyzed plasma samples, obtained periodically during TPN therapy, for choline concentration. Malnourished patients referred to a nutrition support service were prospectively assigned to be treated with daily infusions of amino acids with, and without, supplemental daily infusions of lipid emulsion for a period of 1 wk. After the first week, all subjects received intravenous lipid, and most were offered enteral food supplements. Initial plasma choline concentrations in the 25 malnourished patients were significantly lower than those measured in plasma samples from 23 hospitalized patients known to be eating well (6.5 +/- 0.6 vs 9.7 +/- 0.7 nmol/ml; mean +/- SEM; p less than 0.001). During the first week of TPN therapy, plasma choline concentrations in the lipid-restricted group tended to decrease (from 7.3 +/- 1.0 to 4.7 +/- 0.5 nmol/ml; mean +/- SEM; p less than 0.05), while in the lipid-supplemented group plasma choline tended to increase (from 5.6 +/- 0.5 to 6.2 +/- 0.7 nmol/ml; mean +/- SEM; p less than 0.05). Plasma choline concentration increased during wk 2-4, when all patients were treated with lipid emulsions, and some were offered enteral foods. We conclude that malnourished humans who eat no choline have diminished stores of plasma (and possibly tissue) choline.
Dimethylamine is important because it is a precursor of nitrosodimethylamine, a suspected carcinogen in man. Significant quantities of dimethylamine and nitrite are found in gastric fluid, and conditions in the stomach are favorable for nitrosodimethylamine formation. Little is known about the origins of dimethylamine in gastric fluid. Studies were performed to determine whether dimethylamine can be transported from blood to gastric fluid. There was no diurnal variation of the dimethylamine content in gastric fluid or blood from untreated dogs. We administered 50 mg/kg dimethylamine i.v. to dogs and ferrets and collected blood and gastric fluid samples at timed intervals. In both species we observed similar kinetics of dimethylamine distribution into biologic fluids. Dimethylamine concentrations in blood and gastric fluid rose rapidly during the first minutes after treatment. Blood dimethylamine concentrations peaked within 30 min after the dose (rising from 10 to 430 nmol/ml in the dogs, and from 30 to 430 nmol/ml in the ferrets). Dimethylamine concentrations in blood slowly decreased thereafter. Gastric fluid dimethylamine concentrations continued to rise for 3 h after the dose (from 40 to 540 nmol/ml in the dogs, and from 40 to 1056 nmol/ml in the ferrets). Gastric fluid dimethylamine remained elevated for more than 5 h. Between 1 h and 5 h after treatment, gastric fluid dimethylamine concentrations were significantly higher than blood dimethylamine concentrations (by greater than 2.5 X). In gastric fluid from control animals, dimethylamine concentration exceeded monomethylamine concentration, which in turn was higher than trimethylamine concentration. Administration of dimethylamine transiently increased gastric fluid monomethylamine content, but had little effect upon trimethylamine concentration. These data demonstrate that dimethylamine is efficiently transported from blood into gastric fluid.
Choline is a precursor for the biosynthesis of phosphatidylcholine (lecithin), sphingomyelin, and choline plasmalogens--all essential constituents of membranes. Choline is also needed to make acetylcholine, a major neurotransmitter. The major choline-containing compounds of human milk (unesterified choline, phosphatidylcholine, sphingomyelin) were measured in samples obtained from mothers of full-term infants. Unesterified choline concentrations were highest (greater than 600 nmol/ml) during the first week of lactation, but thereafter remained relatively constant at 70-200 nmol/ml. There was no difference among foremilk, middle milk and hind milk, nor was there a diurnal pattern of variation in unesterified choline concentrations. Milk phosphatidylcholine and sphingomyelin concentrations remained relatively constant throughout lactation (100-200 nmol/ml). Hind milk always contained more of these phospholipids than did foremilk or middle milk. There was no consistent diurnal pattern of variation in milk concentrations of phosphatidylcholine or sphingomyelin. Milk contained no phospholipase activity capable of forming free choline from phosphatidylcholine or sphingomyelin. Bovine milk contained approximately the same concentrations of choline, phosphatidylcholine and sphingomyelin as did human milk from mothers more than 15 d postpartum. The same was true of "humanized" infant formulas made from cow's milk. Soy protein-based formulas had much more unesterified choline (up to 650 nmol/ml) and much less sphingomyelin than did mature human milk.
We studied choline uptake by slices of adult and 10-day-old rat intestine which were exposed on their mucosal surface to radiolabeled choline. Both neonatal and adult intestine transported choline. Choline uptake was observed in duodenum, jejunum, ileum, and colon of the adult rat. In the small intestine, choline uptake consisted of two components: a saturable and a nonsaturable process. The kinetic variables for saturable transport (Km, Vmax) were not significantly different in adult and neonatal small intestine. Some of the transported choline was converted to phosphatidylcholine, glycerophosphocholine, phosphocholine, and betaine. However, most of the transported choline (79-85%) was not metabolized within the intestinal slice during a 15-min period. We conclude that the capacity for choline transport in the rat small intestine is present early in neonatal life. The characteristics of this transport mechanism for choline are similar in the neonate and in the adult small intestine. Neonates should therefore be able to absorb the large amounts of unesterified choline that are present in milk.
Diet clearly influences neurotransmission. This can be important in grossly undernourished children. It can also be important in children in whom normal homeostatic mechanisms governing food intake are bypassed. Subtle differences in behavior can occur with physiologic variation in food intake. Components of foods can also be used as drugs. Starvation can impair neuronal maturation and can have lasting effects upon behavior and intellectual performance. The extent of starvation's impact upon the brain depends upon whether undernutrition occurred during a critical phase in brain development. Short-term fasting has small, but significant, effects upon intellectual performance. Even when gross malnutrition is not present, subtle changes in diet may modulate brain function. Tryptophan, tyrosine, and choline in the diet are used as precursors for neuronal synthesis of serotonin, dopamine and norepinephrine, and acetylcholine, respectively. It is likely that the brain's sensitivity to certain components of the diet exists to permit monitoring of food intake by the central nervous system. Tryptophan, tyrosine, and choline may be useful in treatment of humans with sleep disorders, pain depression, mania, hypertension, shock, or dyskinesias. Other components of the diet that may affect behavior include food additives, sugar, and caffeine. Food additives may exacerbate hyperactive symptoms in a small proportion of children with attention deficit disorder. Given that there is little potential for harm and that there is a subpopulation that may respond, a trial of a diet that contains no food additives may be a valid diagnostic approach for children with attention deficit disorder who do not respond to stimulant therapy or for children for whom stimulant therapy is not desired. Refined sugar has been blamed for many behavioral abnormalities. Subtle effects of carbohydrate upon behavior have been reported, but the existing data do not support the hypothesis that sucrose or fructose exert special effects upon neurotransmission. Caffeine is easily detected as a stimulant by humans, but it has little effect upon cognitive function. Administration of large doses of vitamins has no beneficial effect in most humans with schizophrenia, attention deficit disorder, autism, Down's syndrome, or drug addiction. Large doses of niacinamide may even be harmful, as they may cause hepatic damage.
Consumption of fish has been encouraged recently because it may prevent mortality due to heart disease. Fish contains methylamines, which are precursors of N-nitrosamines. Nitrosamines can act as potent carcinogens in a wide variety of animal species, and there is no reason to assume that humans are resistant. Human subjects (n = 5) ingested a diet of known methylamine content for 2 days. On Day 3, they ate fish at the luncheon and dinner meals. On Day 4, they again ate the control diet. A single portion of fish contained as many methylamines as were normally excreted by the human in 2 days. Urinary excretion of monomethylamine remained constant (1.3 to 1.5 mumol/24 h/kg of body weight) throughout the study. Dimethylamine excretion increased more than 4-fold after fish was eaten (from 5.6 to 24.1 mumol/24 h/kg of body weight), while trimethylamine excretion increased more than 8-fold (from 0.2 to 1.6 mumol/24 h/kg of body weight). We conclude that the consumption of fish significantly increased exposure to methylamines, particularly to dimethylamine. Although there is potential for the in vivo conversion of dimethylamine to nitrosodimethylamine, a carcinogen, we know of no studies that have determined that the ingestion of fish increases the risk of cancer. This should be carefully investigated prior to recommending that humans change their eating habits.
An understanding of the biosynthesis and metabolism of dimethylamine (DMA) is important because it is a precursor of dimethylnitrosamine (nitroso-DMA). DMA is the major short-chain aliphatic amine in human and rat urine. DMA is formed from trimethylamine (TMA), which, in turn, is a breakdown product of dietary choline. Enzymes within gut bacteria catalyse both of these reactions; it is not known whether mammalian cells can form DMA. To determine the relative importance of dietary choline, bacteria and other mechanisms for the formation of DMA, we measured DMA excretion in the urine of rats fed on a diet devoid of choline, and in urine of rats with no bacterial colonization of the intestines. We also describe an improved gas-chromatographic method for the measurement of methylamines in biological fluids. In control rats there were significant amounts of DMA within several biological fluids [urine, 54.2 +/- 3.0 mumol/kg body wt. per 24 h (556.2 +/- 37.5 nmol/ml); blood, 18.8 +/- 1.9 nmol/ml; gastric juice, 33.5 +/- 10.5 nmol/ml; means +/- S.E.M.]. Animals eating a diet containing no choline excreted as much MMA and DMA as did choline-supplemented rats (25-35 mumol/kg per 24 h), and they excreted slightly less TMA (2 versus 2.5 mumol/kg per 24 h). Rats with no gut bacteria excreted the same amount of DMA in their urine as did the control animals (45-55 mumol/kg per 24 h). They excreted much less MMA (16.3 +/- 1.5 versus 40.3 +/- 2.6 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01), TMA (0.7 +/- 0.2 versus 2.5 +/- 0.5 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01) and piperidine (2.0 +/- 0.3 versus 6.3 +/- 0.6 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01) in their urine. From our studies we conclude that DMA is present in significant amounts within gastric fluid, an environment that is ideal for nitrosamine formation (under acidic conditions, nitroso-DMA is chemically formed by the reaction of nitrite with DMA). Results also indicate that dietary choline was not the sole precursor for DMA formation and that gut bacteria are not essential for the formation of DMA. Hence in mammals there must be endogenous pathways that are capable of forming DMA; however, these endogenous mechanisms remain unidentified.
The activity of phosphatidylethanolamine N-methyltransferase (PeMT), an enzymic system that catalyses the synthesis of phosphatidylcholine (PtdCho) via sequential methylation of phosphatidylethanolamine (PtdEtn) using S-adenosylmethionine (AdoMet) as a methyl donor, was examined in brain homogenates from rats of various ages. The data thus obtained were consistent with the existence of two distinct enzyme activities within this enzyme system, i.e. one catalysing the methylation of PtdEtn [to form phosphatidyl-N-monomethylethanolamine (PtdMeEtn)], and the other catalysing the methylations of PtdMeEtn and phosphatidyl-NN-dimethylethanolamine (PtdMe2Etn) (to form PtdMe2Etn and PtdCho, respectively). PeMT (PtdEtn-methylating) activity per g of brain was 4-fold higher in neonatal than in adult brains. The enzyme activity in adult brains exhibited Michaelis-Menten kinetics for AdoMet, and its affinity for AdoMet was high (apparent Km 1.6 microM). In neonatal brain the relationships between AdoMet concentrations and PtdMeEtn formation were more complex: a sigmoidal component (with a Hill coefficient of 2.7), requiring 90 microM-AdoMet for half-saturation predominated over the high-affinity component (similar to that of the adult brain). PeMT (PtdMe2Etn-methylating) activity per g of brain increased 2-fold between the 5th and the 20th postnatal days and remained constant thereafter; it was higher than that of PeMT (PtdEtn-methylating) activity at all ages studied, and its affinity for AdoMet was low (apparent Km 99 microM). No sexual dimorphism in brain PeMT activity was observed at any age. We conclude that PeMT (PtdEtn-methylating) catalyses the rate-limiting step in PtdCho synthesis in rat brain, and that PtdCho formation via this pathway may be greatest during the neonatal period.
Two preparations of rat brain (ischemic intact brain and homogenized whole brain) formed large amounts of unesterified (free) choline when incubated at 37 degrees C. The accumulation of choline was inhibited by microwave irradiation of brain, or by heating of brain to 50 degrees C, and was maximal at 37 degrees C at pH 7.4-8.5. Choline formation was only observed in subcellular fractions of brain that contained membranes. In homogenates of brain, choline accumulated at a rate exceeding 10 nmol/mg protein per h. There was a significant decrease in brain phosphatidylcholine concentration (of 50 nmol/mg protein) during incubation for 1 h at 37 degrees C. Concentrations of phosphocholine rose (by 2.3 nmol/mg protein), and concentrations of glycerophosphocholine and sphingomyelin did not change during this period. We used radiolabeled phospholipids to trace the fate of phosphatidylcholine and sphingomyelin during incubations of homogenates of brain. Phosphatidylcholine was degraded to form phosphocholine, glycerophosphocholine and free choline. No lysophosphatidylcholine accumulated. Sphingomyelin was degraded to form phosphocholine and a small amount of free choline. Magnesium ions stimulated choline production, while zinc ions were a potent inhibitor. Other divalent cations (calcium, manganese) had little effect on choline accumulation. ATP concentrations in brain homogenates were less than 5 nmol/mg protein (rapidly microwaved brain contained 27 nmol/mg protein). Addition of ATP or ADP to brain homogenates increased ATP concentrations and significantly inhibited choline accumulation. ATP diminished the formation of choline from added phosphatidylcholine, lysophosphatidylcholine, phosphocholine and glycerophosphocholine. The effects of ATP, zinc ion, or magnesium ion upon choline accumulation were not mediated by changes in the rates of utilization of choline for formation of phosphocholine or phosphatidylcholine. In summary, we showed that there was enhanced formation of choline when ATP concentrations within brain were low. This choline was derived, in part, from the degradation of phosphatidylcholine, and we suggest that phospholipase A activity was the primary initiator of choline release from this phospholipid.
In recent years, short-term effects of the composition of each meal on the synthesis of brain neurotransmitters have been studied. This paper reviews studies of the influence of dietary precursors such as tryptophan and other competing amino acids on serotonin synthesis and metabolism and emphasizes the important influence of insulin. The paper then focuses on assessment of newborn state behavior, since evidence in adult humans has suggested a relationship between sleep behavior and brain serotonin levels. Several studies are then summarized. First, a study of healthy full-term newborns examining the relationship between diet and sleep behavior showed that infants fed tryptophan entered active and quiet sleep sooner than infants fed valine and low carbohydrate. Other studies designed to examine the influence of hyperinsulinemia on this system are then described. An observational study of newborns of diabetic mothers during the first weeks of life showed that they were quieter babies, with difficulties in visual orientation and motor performance. Plasma amino acid ratios studied during a glucagon-stimulation test in an infant with hyperinsulinemia showed a marked increase in parallel with changes in insulin levels. The results suggest that infant sleep behavior can be a sensitive dependent variable in studies of behavioral effects of diet and suggests that variations in serotonin levels may play a modulating role.
Sleep behavior is modulated by serotonergic neurons within the brain, and the synthesis and release of serotonin by such neurons is thought to be influenced by the availability of tryptophan, the amino acid precursor of serotonin. We investigated the effects on the sleep patterns of newborn infants of variations in diet designed to affect tryptophan availability. Twenty healthy newborns (two to three days of age) were randomly assigned to receive a feeding consisting either of tryptophan in 10 per cent glucose or valine in 5 per cent glucose (valine competes with tryptophan for entry into the brain). Sleep patterns during the three hours after this feeding were compared with those after a feeding of routine formula (Similac). The infants fed tryptophan entered active sleep 14.1 minutes sooner than they did after Similac, and entered quiet sleep 20 minutes sooner. Those fed valine entered active sleep 15.8 minutes later than they did after Similac, and entered quiet sleep 39 minutes later. The differences between the tryptophan and valine groups were significant (P less than 0.01 for active sleep and P less than 0.005 for quiet sleep). We conclude that variations in the composition of the diet may influence sleep behavior in newborns.
Humans ingest substantial amounts of choline and lecithin as part of common foods. Physicians have recently begun administering large doses of these compounds to individuals with neurological diseases. A significant fraction of ingested choline is destroyed by enzymes within gut bacteria, forming trimethylamine (TMA), dimethylamine (DMA) and monomethylamine (MMA). Some of these methylamines are eventually excreted into the urine, presumably after being absorbed and carried to the kidneys via the bloodstream. The methylamines formed after choline is eaten could be substrates for the formation of nitrosamines, which have marked carcinogenic activity. Twenty-seven millimoles of choline chloride, choline stearate or lecithin were administered to healthy human subjects. It was found that these treatments markedly increased the urinary excretion of TMA, DMA and MMA, with choline chloride having the greatest effect. Rats were treated with 2 mmol/kg b.wt. of choline chloride or lecithin, and it was found that these treatments significantly increased urinary TMA excretion and did not alter DMA or MMA excretion. Our choline chloride preparation contained no MMA, DMA or TMA; however, it was found that our choline stearate and all the commercially available lecithins tested were contaminated with methylamines. Prior removal of methylamines from our lecithin preparation minimized the effect of oral administration of this compound on methylamine excretion in urine of rats and humans.
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