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Biomedical subjects

O Greengard

Publications and source records attributed to O Greengard.

At least 55 records · Page 3Linked to original sources
PubMed1980

Adenylate kinase isoenzyme patterns in normal and neoplastic human lung, and in various adult as compared to fetal rat tissues.

The isozyme pattern and total activity of adenylate kinase were studied in normal adult and fetal human and rat tissues using starch gel electrophoresis. Three adenylate kinase isoenzymes were identified in human tissues. Although normal adult lung exhibited higher adenylate kinase activity than did its fetal or neoplastic variant, isozyme patterns in the three types of tissues were indistinguishable from each other and from that in fetal human liver. The pattern of these three isozymes in rat lung (as in spleen) also did not change between fetal and adult life. However, adult kidney and heart of this species did appear to contain isozymes not present in fetal life. Brain (both adult and fetal) was striking different from all the other tissues in that it contained only one adenylate kinase isozyme. The total adenylate kinase activity per gram of adult rat liver, kidney and lung was significantly higher than in the cognate fetal organs, whereas that in brain or spleen did not change with age. The activity in adult heart (similar to the fetal one) was higher than in any other tissue examined.

Adenylate Kinase↗
PubMed1980

Uridine kinase, adenylate kinase, and guanase in human lung tumors.

In pulmonary neoplasms, the uridine kinase concentration was higher (2- to 20-fold) than in the noninvolved lung portions of each of the 12 subjects studied. The extent of elevation of uridine kinase in the different tumors showed a significant positive correlation with the rises (1.5- to 30-fold) in thymidine kinase, suggesting that neoplastic transformation in human lung involved coordinated increases in the capacity for the reutilization of different nucleoside phosphates. Adenylate kinase was always at lower levels in neoplasms compared to noninvolved areas of the same lung, and the extent of this loss in the different tumors correlated inversely with the gain in uridine kinase and thymidine kinase. Normal fetal human lung was also deficient in adenylate kinase, while its uridine kinase and thymidine kinase (and also guanase) activities were above the adult levels. The guanase activities of the different neoplasms, unrelated to their uridine kinase or thymidine kinase content, correlated with the activities in the subjects' noninvolved lung. These individual differences were much more striking than those between the neoplastic and control samples. Variations in guanase activity thus appear to be "random," whereas observations on the three other enzymes attest to the orderly nature of biochemical differences among individual tumors and between normal and neoplastic lung.

Adenocarcinoma↗
PubMed1980

Phosphotransferases and lysosomal enzymes in fetal human and rat lung.

The present investigations on rat lung show that metabolic changes occurring around the 20th gestational day are accompanied by multiple alterations in the quantitative pattern of enzymes. This involves increases in two lysosomal enzymes (N-acetyl beta-glucosaminidase and beta-galactosidase) and a rise and fall in pyruvate kinase and alpha-glucosidase. The striking transient upsurge of adenylate kinase, however, is postponed until after birth. The normal diminution of thymidine kinase and peptidylproline hydroxylase is drastically enhanced by an injection of cortisol to fetal rats. Studies on human pulmonary tissues consisted in determining enzyme concentration from the ninth to the 21st week of gestation and an histologically normal adult lungs. The results show that the 15th to the 21st week of gestation is the period of increase in pyruvate kinase, adenylate kinase and alpha-glucosidase. The rise during the development of several enzymes (e.g., 5'-nucleotidase, alkaline phosphatase, and gamma-glutamyl transpeptidase) and the decline in thymidine kinase and peptidylproline hydroxylase, however, dose not begin until after the 21st week of gestation.

Acetylglucosaminidase↗
PubMed1978

Comparison of alpha-methylphenylalanine and p-chlorophenylalanine as inducers of chronic hyperphenylalaninaemia in developing rats.

alpha-Methylphenylalanine is a very weak competitive inhibitor of rat liver phenylalanine hydroxylase in vitro but a potent suppressor in vivo. The loss of the hepatic activity (the renal one is unaffected) becomes maximal (70-75% decrease; cf. control) 18h after the administration (per 10g body wt.) of 24 mumol of alpha-methylphenylalanine with or without 52 mumol of phenylalanine. Chronic suppression of hepatic phenylalanine hydroxylase was obtained by injections of alpha-methylphenylalanine plus phenylalanine to suckling rats, and by their addition to the diet after weaning. A series of comparisons of the effects of this treatment, and one with p-chlorophenylalanine, was then carried out. In both cases there was a rise (1.3-2-fold) in phenylalanine-pyruvate amino-transferase activity (but no change in four other enzyme activities) in the liver; in brain there was a rise in phosphoserine phosphatase activity, but the total activity and subcellular distribution of nine enzymes revealed no other abnormalities in cerebral development. Striking increases in the concentration of plasma phenylalanine during 26 of the 31 experimental days (with a transient fall at 18-22 days) were maintained by treatment with both analogues plus phenylalanine. However, p-chlorophenylalanine-treated animals had a 30-60% mortality rate and 27-52% decrease in body weight. Developing rats treated with alpha-methylphenylalanine, showing no growth deficit or signs of toxicity (e.g. cataracts), appear to be a more suitable model for the human disease of phenylketonuria. Their phenylalanine concentrations exhibited at least 20-40-fold increase during 50% of each of the first 18 days of life, and 30-fold after weaning.

Animals↗
PubMed1978

Human colon tumors: enzymic and histological characteristics.

In samples of colonic adenocarcinomas, the mean activities of thymidine kinase, glucose-6-phosphate dehydrogenase, phosphoserine phosphatase and pyrroline-5-carboxylate reductase were several fold higher than those of nonneoplastic colon. The presence of considerable, cold labile pyrroline-5-carboxylate reductase activity provided an additional criterion for distinguishing tumors from the control tissue. Deviations from the pattern of enzymes in normal colon were much more pronounced in the five moderately well-differentiated than in the single well-differentiated adenocarcinoma.

Adenocarcinoma↗
PubMed1978

Tissue enzyme changes in parabiotic rats with subcutaneous lymphoma or fibrosarcoma.

A solid lymphoma implanted into normal inbred Kx rats and one partner of parabiotic pairs caused appreciable decreases in hepatic ornithine aminotransferase and arginase about a week earlier (4-6 days after implantation) in single hosts than in parabiotic hosts. By 18-21 days significant decreases in both enzymes were apparent in the host partner also. The hepatic thymidine kinase showed a fivefold elevation in single hosts 4 days after implantation; by 14 days in its levels were about 200 times above normal and had also risen in the parabiotic hosts (20-fold) and host partners (fourfold). Implantation of fibrosarcoma caused qualititatively similar but generally less pronounced changes in these three enzymes in livers of single hosts, parabiotic hosts, and host partners. The splenic thymidine kinase 14 days after implantation was increased from control levels of about 3 U/g to 50.6, 44.8, and 13.5 U/g in single hosts, parabiotic hosts, and host partners, respectively. At later stages, 17-20 days after implantation of the lymphoma, appreciable amounts of thymidine kinase appeared in the plasma: The units of activity per milliliter were 6.2 in single hosts, 0.79 in parabiotic hosts, and 0.55 in host partners (control less than 0.05). Our observations on the changes in hepatic and splenic enzymes in parabiotic rats suggest that effects of neoplasms on distant host tissues are mediated by humoral factors. The less pronounced responses in parabiotic than in single hosts indicate that the tumor-free partner affords some "protection" against these systemic effects.

Animals↗
PubMed1978

Dihydropteridine reductase activity of adult, fetal and neoplastic tissues.

Optimal conditions for the assay of dihydropteridine reductase in crude tissue extracts have been developed. Among adult rat tissues, liver and kidney had the highest activity followed by thymus, lung, cerebellum and cerebrum. Fetal tissues and neoplasms exhibit lower activities than the cognate adult tissues. In both liver and kidney the developmental upsurge of dihydropteridine reductase, which produces the cofactor necessary for the hydroxylation of aromatic amino acids, begins earlier than does that of phenylalanine hydroxylase. In human liver and lung also, the dihydropteridine reductase activity doubles between midgestation and adult life. The undifferentiated enzymic composition of neoplasms is reflected by the lower dihydropteridine reductase content of pulmonary tumors than of nonneoplastic human lung.

Adult↗
PubMed1977

Distribution of mitochondrial enzymes between the perikaryal and synaptic fractions of immature and adult rat brain.

The subcellular distribution of mitochondrial enzymes was studied in cerebral hemispheres of 15-day-old and adult rats. At both ages the synaptosomal fraction contained very little glutamate dehydrogenase (EC 1.4.1.2) but significant amounts of succinate dehydrogenase (EC 1.3.99.1), glutaminase (EC 3.5.1.2), hexokinase (EC 2.7.1.1), malate NADP dehydrogenase (EC 1.1.1.40) and beta-hydroxybutyrate dehydrogenase (EC 1.1.1.30). In immature brain, in the fraction enriched with free (perikaryal) mitochondria, the concentrations of these enzymes were 9.5, 1.8, 2.0, 0.92, 1.5, and 2.1 times higher, respectively, than in the synaptosomes. The increase with age in succinate dehydrogenase and glutaminase was restricted to free mitochondria while hexokinase and malate NADP dehydrogenase accumulated and beta-hydroxybutyrate dehydrogenase diminished in both fractions. In adult brain, too, where the above ratios became 7.5, 5.2, 3.5, 0.84, 1.4, and 2.0, respectively, the concentrations of enzymes relative to each other distinguished clearly between free and synaptic mitochondria. The results substantiate previously noted signs of mitochondrial heteroeneity in adult brain, and extend them to immature brain. The chemical composition, the quantitative pattern of enzymes, of free and synaptic mitochondria is clearly different, and undergoes separate changes during postnatal differentiation.

Aging↗
PubMed1977

Enzymic differentiation of human liver: comparison with the rat model.

The quantitative pattern of enzymes in the second trimester human fetal liver is significantly different from that of adult liver. For some 20 enzymes, the activity quotient (AQ, i.e., activity of immature liver divided by that in adult liver) is appreciably different from 1.0. Most of the enzymes increase their concentrations with age but, as one would expect, some contribute to differentiation by diminishing in amount. In developing human liver the concentrations of the various enzymes tend to change in the same direction as they do in rat liver. Those that increase in rat liver have been classified into three main clusters, according to whether their rise begins on about the 17th day of gestation (B), the first neonatal day (C), or just before weaning (D), respectively. The distribution of these enzymes among these three clusters correlates with their AQ's in the human fetal liver. In general, enzymes with AQ around 0.5 belong to cluster (B) in rat liver whereas those with 0-0.16 belong to cluster C or D. Gross malformations resulting from the teratogenic action of drugs, hormones, or vitamins on the early embryo attract much attention. The harmful impacts of such agents at late stages of gestation are less spectacular. They may be more frequent, however, and manifest themselves in permanent inadequacies in metabolism or growth with a tendency to succumb to minor childhood diseases. The underlying causes may not be mirrored in the cytocomposition or even the subcellular morphology of autopsy specimens. Only deviations from the organ characteristic quantitative pattern of gene products would provide sensitive enough indictors of the metabolic lesions and of the aberrant aspects of differentiation that were responsible for them. In both the presence and absence of detectable morphologic abnormalities, the study of enzymes, this most varied and largest class of specific chemical constituents, would greatly extend the resolving power of the usual diagnostic procedures postmortem.

Animals↗
PubMed1977

Phenylalanine hydroxylase and tyrosine aminotransferase in human fetal and adult liver.

The mean value of phenylalanine hydroxylase activity in adult human liver was almost twice as high as that in the fetal ones; no consistent variations were seen with sex, fetal age (between the 11th and 22nd week of gestation), or with hours between delivery and death. The tyrosine aminotransferase levels did not correlate with sex, age, or method of abortion; however, they were 5 times higher in the two fetuses which survived for more than 1.5 hr after delivery. The mean concentration of tyrosine aminotransferase (excluding these two fetuses) was about 15 times lower than in the adult liver. Phenylalanine hydroxylase is known to appear in rat liver on the 20th to 21st day of gestation. Tyrosine aminotransferase, on the other hand, emerges on the first postnatal day and, as shown here, can be evoked by premature delivery. Thus, in man as in the rat, (1) phenylalanine hydroxylase approaches physiologically significant levels at an earlier development stage than does tyrosine aminotransferase and (2) extrauterinization stimulates the synthesis of tyrosine aminotransferase but not of phenylalanine hydroxylase. Speculation There is a greater analogy than is usually assumed between human and rat liver with respect to the time schedule of enzymic differentiation and the factors which regulate it.

Adult↗
PubMed1977

The effect of lymphoma and other neoplasms on hepatic and plasma enzymes of the host rat.

Considerable thymidine kinase and pyrroline-5-carboxylate reductase activities were found in the plasma of rats bearing a transplanted lymphoma; neither activity was detected in plasma of hosts carrying hepatic, renal, mammary, or submaxillary gland tumors. All host livers exhibited signs of biochemical immaturity as indicated by the appropriate increases or decreases in the concentrations of the nine enzymes measured. The extent and time schedule of the changes in host liver varied with the enzyme and with the tumor that caused them. The hepatic concentrations of ornithine aminotransferase, arginase, pyrroline-5-carboxylate reductase, and glucokinase (all diminished), and of peptidyl proline hydroxylase and hexokinase (increased) were sensitive indicators of tumor growth in general. The concentration of ornithine aminotransferase decreased before the tumors became palpable. At more advanced stages, the high hepatic thymidine kinase activity distinguished the presence of hepatoma and lymphoma from those of all other equally fast-growing tumors. However, only in lymphoma-bearing rats did a fivefold elevation of hepatic thymidine kinase occur as early as 4 days after implantation. Additional observations on the lymphoma itself, on blood cells, and on the involuting thymus of normal rats indicate that the striking systemic effects of this tumor cannot be explained by a release of enzymes from the thymus or by the increased number of lymphoma cells present in blood or liver.

Animals↗
PubMed1977

The undifferentiated enzymic composition of human fetal lung and pulmonary tumors.

The concentrations of 16 to 21 enzymes, representing various metabolic pathways, have been determined in human adult, fetal, and neoplastic lung. At midgestation, 12 enzymes (among them, several that metabolize amino acids) were above their adult values while 3 other enzymes were still at low concentrations. These signs of biochemical immaturity are contrasted and compared with those in fetal human liver and rat lung. The enzymic composition of the 11 human pulmonary tumors studied resembled that of the normal fetal lungs closely; the same 12 enzymes were elevated and the same 2 were decreased (compared to nonneoplastic adult lung) in both. The characteristic abnormality in the overall pattern of enzymes, in the concentrations of individual ones, and in the quality of pyrroline-5-carboxylate reductase was clearly evident in both primary and metastatic tumors. The mean concentrations of 10 enzymes in the tumors were significantly different (higher or lower) from those in the control lungs (p less than 0.001 to less than 0.05). The best markers of neoplasticity were thymidine kinase, peptidyl proline hydroxylase, phosphoserine phosphatase, hexokinase, and pyrroline-5-carboxylate reductase. The results demonstrate that quantification of a small battery of enzymes, none of them tissue specific, can distinguish adult human lung from its neoplasms.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1976

The regulation of phenylalanine hydroxylase in rat tissues in vivo. The maintenance of high plasma phenylalanine concentrations in suckling rats: a model for phenylketonuria.

Maximum inhibition of phenylalanine hydroxylase activity in the liver (85%) and in the kidney (50%) of suckling rats required the administration of over 9 mumol of p-chlorophenylalanine/10g body weight. Despite the decrease in the total activity from 184 to 34 units per 10g body weight, the injection of as much as 26 mumol of phenylalanine was required for its concentration in plasma to be still considerably elevated 12h later. In rats injected with p-chlorophenylalanine every 48h and with phenylalanine every 24h from 3 to 18 days of age, the hepatic and renal phenylalanine hydroxylase remained inhibited, whereas the activities of three other hepatic enzymes were unchanged. There was about 20% inhibition of brain and body growth, but no interference with the developmental formation of several cerebral enzymes (four dehydrogenases, hexokinase and glutaminase) was detected. In the course of this prolonged treatment, the phenylalanine concentrations in plasma increased gradually; on day 2 and day 8 (measured 12h after the last injection) they were 800 and 1395 nmol/ml respectively; on day 15, 12 and 18h after the usual injection, the values were 2030 and 1030 respectively as opposed to the 96 nmol in untreated rats. This degree of hyperphenylalaninaemia, persisting for 18h per day throughout a critical period of development, fulfils the primary criterion of a suitable animal model for phenylketonuria.

Animals↗
PubMed1976

The regulation of phenylalanine hydroxylase in rat tissues in vivo. Substrate- and cortisol-induced elevations in phenylalanine hydroxylase activity.

Injections of phenylalanine increased a 2.5-fold in 9 h the hepatic phenylalanine hydroxylase activity of 6-day-old or adult rats that had been pretreated (24h earlier) with p-chlorophenylalanine; without such pretreatment, phenylalanine did not raise the enzyme concentration. This difference is paralleled by the much greater extent to which the injected phenylalanine accumulated in livers of the pretreated compared with the normal animals. The hormonal induction of hepatic phenylalanine hydroxylase activity obeyed different rules: an injection of cortisol was without effect on adult livers but caused a threefold rise in phenylalanine hydroxylase activity of immature ones, both without and after pretreatment with p-chlorophenylalanine. In the latter instance, the effects of cortisol, and of phenylalanine were additive. Actinomycin inhibited the cortisol- but not the substrate-induced increase of phenylalanine hydroxylase, whereas puromycin inhibited both. The results indicate that substrate and hormone, two potential positive regulators of the amount of the hepatic (but not the renal) phenylalanine hydroxylase, act independently by two different mechanisms. The negative effector, p-chlorophenylalanine, also appears to interact with the synthetic (or degradative) machinery rather than with the existing phenylalanine hydroxylase molecules: 24h were required in vivo for an 85% decrease to ensue, and no inhibition occurred in vitro when incubating the enzyme with p-chlorophenylalanine or with liver extracts from p-chlorophenylalanine-treated rats.

Animals↗