Search PubMed⌕ Search

Biomedical subjects

D M Goldberg

Publications and source records attributed to D M Goldberg.

At least 91 records · Page 5Linked to original sources
PubMed1981

Effects of phenobarbital upon triacylglycerol metabolism in the guinea pig.

The association between hepatic microsomal enzyme induction and triacylglycerol metabolism was examined in fasting male guinea pigs injected intraperitoneally with 50 mg phenobarbital x kg-1 for 7 days. Enzyme induction was established by a significant increase in hepatic aminopyrine N-demethylase activity, cytochrome P450 content, and hepatic gamma-glutamyl-transferase activity. Increased activity of gamma-glutamyltransferase was also observed in the blood serum of treated animals. The phenobarbital-treated guinea pigs manifested increased hepatic triacylglycerol content and serum triacylglycerol concentration, accompanied by enhanced ability of cell-free fractions of liver to synthesize glycerolipids in vitro from sn-[14C]glycerol 3-phosphate and fatty acids. Microsomal phosphatidate phosphohydrolase accounted for 97% of the total liver activity of this enzyme, and its specific activity was 50-fold higher than that of the cytosolic enzyme when each was measured under optimal conditions. Activity of the cytosolic phosphohydrolase per liver doubled and that of the microsomal phosphohydrolase increased by 40% in the phenobarbital-treated guinea pigs. The microsomal, but not the cytosolic enzyme, showed a significant correlation with hepatic triacylglycerol content. Significant correlation was observed between the various parameters of hepatic microsomal enzyme induction and hepatic triacylglycerol content, suggesting that enzyme induction may promote triacylglycerol synthesis and consequent hypertriglyceridaemia in the guinea pig.

Aminopyrine N-Demethylase↗
PubMed1981

Enzyme induction and hepatic glycerolipid synthesis in rats treated with 3-methylcholanthrene.

Fasting male rats fed 3-methylcholanthrene in a daily dose of 40 mg . kg body weight-1 gave evidence of hepatic microsomal enzyme induction after 3 days through significantly increased hepatic aryl hydrocarbon hydroxylase activity, cytochrome P448 content, and characteristic changes in microsomal proteins analysed by sodium dodecyl sulfate--polyacrylamide gel electrophoresis. Concomitantly, activities of aminopyrine N-demethylase and microsomal gamma-glutamyltransferase, which are increased in phenobarbital-treated rats, significantly declined. In contrast to phenobarbital, which has been previously shown to increase hepatic triacylglycerol content and in vitro glycerolipid synthesis, 3-methylcholanthrene did not affect hepatic triacylglycerol content, but did inhibit glycerolipid synthesis by cell-free preparations of rat liver and significantly reduced serum triacylglycerol concentration. Thus, the two prototypical drugs inducing characteristically different changes in microsomal enzyme and hemoprotein response also seem to differ in their effect upon another important microsomal function, hepatic glycerolipid synthesis.

Animals↗
PubMed1981

Acute and chronic effects of naltrexone and naloxone on schedule-controlled behavior of squirrel monkeys and pigeons.

Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.

Animals↗
PubMed1981

Fixed-ratio responding under second-order schedules of food presentation or cocaine injection.

Squirrel monkeys pressed a key under second-order schedules in which every nth response resulted in a 2-sec visual stimulus (n-response fixed ratio; n = 10, 20 or 30); after a minimum fixed-interval of time elapsed (second-order t-min fixed-interval; t = 5 or 60), the completion of a fixed-ratio resulted in both the brief stimulus and either presentation of food or i.v. injection of cocaine. Under a second-order 5-min fixed-interval schedule with 15 intervals per session, rates of responding increased to a maximum and then decreased with increases in the amount of food (from 250 to 4000 mg/presentation) or cocaine (from 25 to 400 micrograms/kg/injection). Cocaine injections maintained higher maximal rates of responding than food presentation. When the brief stimuli were omitted during the 5-min intervals, average rates of responding maintained by cocaine decreased, but those maintained by food presentation did not. The presession administration of cocaine (0.3-1.0 mg/kg i.m.) increased rates of responding maintained by food to about the same level as those maintained by cocaine; these elevated rates did not decrease when the brief stimuli were omitted. Under a second-order 60-min fixed-interval with one interval per session, both food and cocaine maintained relatively high rates of responding even with large amounts of food (7.5-14 g/presentation) or cocaine (375-1500 micrograms/kg/injection). When the brief stimuli were omitted during the 60-min interval, rates of responding maintained by either food or cocaine decreased. Thus, the brief-stimulus presentations were essential for maintaining performance under the second-order 60-min fixed-interval schedule.

Animals↗
PubMed1981

Conditioned taste aversion and operant behavior in rats: effects of cocaine, apomorphine and some long-acting derivatives.

Apomorphine and cocaine and their long-acting derivatives, diisobutyrylapomorphine and Win 35,428 (a fluorine-substituted phenyltropane analog of cocaine), were compared for their effects in producing conditioned taste aversions and altering schedule-controlled behavior in rats. The drugs had qualitatively similar effects in both types of experiments; suitable doses of each drug produced marked decreases in consumption of flavored solutions associated with their injection and suppressed key-press responding maintained under a 30-response fixed-ratio scheduled of food presentation. Potency ratios for apomorphine and cocaine relative to their long-acting derivatives were similar in both experiments; Win 35,428 was approximately 34 times more potent than cocaine, whereas apomorphine and diisobutyrylapomorphine did not differ appreciably in potency. Extending the duration of action of cocaine by administering an initial dose of 53 micromol/kg of cocaine followed by two additional doses of 26.5 micromol/kg at 30-min intervals failed to produce a greater degree of taste aversion than administration of only a single dose of 53 micromol/kg of cocaine. The observations with Win 35,428 and diisobutyrylapomorphine confirm previous work with these compounds and extend its generally to other species of animal and types of behaviors. None of the findings support the view that the potency of a drug in producing conditioned taste aversions is correlated with its duration of action.

Animals↗
PubMed1980

Effects of phenobarbital upon triacylglycerol metabolism in the rabbit.

1. The association between hepatic microsomal enzyme induction and triacylglycerol metabolism was examined in fasting male rabbits (2kg body wt.) injected intra-peritoneally with 50 mg of phenobarbital per kg for 10 days. 2. Occurrence of enzyme induction was established by a significant increase in hepatic aminopyrine N-demethylase activity and cytochrome P-450 content, as well as a doubling of microsomal protein per g of liver and a 54% increase in liver weight. Parallel increments in hepatic gamma-glutamyltransferase (EC 2.3.2.2) activity occurred; these were more pronounced in the whole homogenate than in the microsomes, which only accounted for 12.5% of the total enzyme activity in the controls and 17.0% in the animals given phenobarbital. Increased activity of gamma-glutamyltransferase activity was also observed in the blood serum of the test animals. 3. The rabbits given phenobarbital manifested increased hepatic triacylglycerol content and the triacylglycerol concentration of blood serum was also elevated. These changes were accompanied by a significantly enhanced ability of cell-free fractions of liver from the test animals (postmitochondrial supernatant and microsomal fractions) to synthesize glycerolipids in vitro from sn-[14C] glycerol 3-phosphate and fatty acids, when expressed per whole liver. Relative to the protein content of the fraction, glycerolipid synthesis in vitro was significantly decreased in the microsomes, presumably consequent upon the dramatic increase in their total protein content, whereas no change occurred in the postmitochondrial supernatant, possibly due to the protective effect of cytosolic factors present in this fraction and known to enhance glycerolipid synthesis. 4. Microsomal phosphatidate phosphohydrolase accounted for 85% of the total liver activity of this enzyme and its specific activity was 20-fold higher than that of the cytosolic phosphatidate phosphohydrolase (EC 3.1.3.4), when each was measured under optimal conditions. A significant increase in the activity of both enzymes per whole liver occurred in the rabbits given phenobarbital. A closer correlation between hepatic triacylglycerol content and and microsomal phosphatidate phosphohydrolase, as well as the above observation, suggest that this, rather than the cytosolic enzyme, may be rate-limiting for triacylglycerol synthesis in rabbit liver. 5. Significant correlations were observed between the various factors of hepatic microsomal-enzyme induction (aminopyrine N-demethylase and gamma-glutamyltransferase activity as well as cytochrome P-450 content) and hepatic triacylglycerol content, suggesting that that microsomal enzyme induction may promote hepatic triacylglycerol synthesis and consequently hypertriglyceridaemia in the rabbit.

Animals↗
PubMed1980

Assessment of biochemical tests for bone and liver involvement in malignant lymphoma patients.

A profile of biochemical tests was performed on 72 patients attending a lymphoma clinic. Urinary hydroxyproline excretion was increased in 24 cases at the outset; of these ten had positive clinical or radiological evidence of bone disease at that time, and in a further ten such evidence became available over the next two years. Hepatic involvement was detected among 9 patients at the initial examination. All of these, and a further five who developed liver involvement over the next two-year period had raised activity of serum 5'-nucleotidase. Total serum alkaline phosphatase was raised in 8 of the 9 patients with initial involvement, but only 1 of the 11 patients who subsequently developed hepatic disease; the heat stability test indicated the presence of the hepatic isoenzyme in these cases. Alkaline phosphatase was raised in 10 of the 20 cases with initial or subsequent evidence of bone disease, heat stability indicating the bone isoenzyme to be predominant. Serum ornithine transcarbamoylase was raised in only 7 patients with initial hepatic involvement, and the aminotransferases were not helpful in identifying lymphomatous involvement of the liver.

Adult↗
PubMed1980

Structural, functional, and clinical aspects of gamma-glutamyltransferase.

GGT catalyses the transfer of gamma-glutamyl residues to amino acids or small peptides. A number of publications report the purification of GGT, the rat kidney enzyme being the best characterized. Bromelain treatment liberates an active form with a molecular weight of 68,000 separable into two nonidentical glycopeptides with molecular weights of 46,000 and 22,000; the latter contains the gamma-glutamyl binding site. GGT is intimately concerned in the synthesis and metabolism of glutathione through the gamma-glutamyl cycle. There is good evidence that this plays a role in the absorption of amino acids from the glomerular filtrate and from the intestinal lumen through a translocation mechanism. Many studies indicate that the GGT content of liver is increased by enzyme-inducing drugs and that this increase is reflected in elevated activity of the enzyme in blood serum. The serum assay has potential in monitoring drug compliance. Increased serum GGT activity encountered in chronic alcoholics seems to be partly due to microsomal enzyme induction. Utility of the assay in detecting alcoholism is controversial, but it is a useful index to compliance with therapy. Dramatic increases in activity are found in many chemically-induced animal tumors, and can be recognized in premalignant cells long before any morphological changes become evident. It has been used as a test for hepatic metastases, but its predictive value has shown a wide range in the hands of many authors. A similar controversy applies to its role in monitoring cancer therapy. Many synthetic substrates have been used to measure serum GGT activity. Currently, L-gamma-glutamyl-p-nitroanilide is the most popular. Males have higher values than females; activity is very high in the neonate and rather low in pregnancy. The most universal application of serum GGT assay is in diagnosis of liver and biliary tract disease. It is widely believed that higher values occur in biliary obstruction than in parenchymal disease. However, the percentage incidence of abnormalities and the overlap of values in individual cases in different disease categories are so great that the enzyme cannot be recommended for this purpose. Isoenzyme analyses have been performed in an attempt to improve the diagnostic specificity of the serum GGT assay. Tissue-specific patterns have not been described, and disease-specific patterns cannot be reproduced with confidence. Whereas exciting advances are being made in understanding the molecular structure, mechanism, and functions of the enzyme it has yet to find a genuinely useful diagnostic role substantiated by a convincing body of scientific data.

Adolescent↗
PubMed1980

Further experience with computer-assisted diagnosis of diseases of the liver and biliary tree.

Computer-assisted classification of disease has largely relied upon testing the diagnostic algorithm in the same population from which it was originally derived, as a means of validation. To evaluate the accuracy of a diagnostic program in which discriminant function analysis is used, we applied it to a separate population, selected by different criteria from those used to define the original case material on which the diagnostic program was based. We selected a group of 315 patients having abnormal values for alkaline phosphatase, bilirubin, or aspartate aminotransferase for further biochemical and immunological investigations. We used a computer program involving discriminant function analysis and classification procedures primed with the results of 10 tests obtained on each of 535 patients in a previous series to allocate those 173 new patients who had diseases of the liver or biliary tree into one of 13 disease groups. The classification was less accurate than was the case in previous cross-validation studies. We developed new discriminants with the new case material, using the same group of tests, and when cross-validation was performed, overall accuracy was greatly improved. These experiences point to the powerful influence of group selection upon computer-assisted diagnostic procedures, and the hazards of applying to one clinical population discriminant functions derived from a different population.

Autoanalysis↗
PubMed1979

Lack of value of serum gamma-glutamyl transferase in the diagnosis of hepatobiliary disease.

Serum gamma-glutamyl transferase (GGT, EC. 2.3.2.2. was measured in 173 patients with diseases of the hepatobiliary system (including metastatic cancer) and in 90 patients who were subsequently shown to have primary diseases of other etiology. All patients had been selected because they had abnormal alkaline phosphatase, aspartate aminotransferase or bilirubin on SMA 12/60 screening. Serum GGT was elevated in 97% of patients with primary hepatobiliary disease. The magnitude of the increase in GGT was variable in all groups and was unhelpful in differential diagnosis, even between medical and surgical cases. Moreover, GGT was abnormal in 69 patients who did not have primary hepatobiliary disease (77%), an incidence higher than that for other enzyme tests performed. We conclude that because GGT was more susceptible than other tests to spurious elevation in the absence of hepatobiliary disease and was unhelpful in differential diagnosis, it has little value apart from monitoring alcohol abuse and enzyme induction.

Biliary Tract Diseases↗
PubMed1979

Isoenzymes of hexokinase, 6-phosphogluconate dehydrogenase, phosphoglucomutase and lactate dehydrogenase in uterine cancer.

Electrophoresis of cytosol prepared from normal and malignant tissue samples of uterine cervix and endometrium revealed interesting differences which may be relevant to the characteristic alterations in glucose metabolism associated with tumour development. Hexokinase II was detected in 30% of the cancer material from both sources, but in none of the samples of normal cervix. A duplet band of 6-phosphogluconate dehydrognease was seen in the majority of the cancer samples but in no sample of normal cervix; it appeared to be partly due to ageing of the sample, and is not phenotypically related to the malignant process. Analysis of genetic variance for phosphoglucomutase at the PGM1 locus revealed a highly significant excess of the PGM1-1 phenotype in patients with cancer of the endometrium, which may reflect susceptibility to endometrial cancer in patients with this phenotype. At the PGM2 locus, samples of malignant cervix were deficient in "Band f" compared with normal cervix samples, all of which showed this band. Conversely, gene products of the PGM3 locus were found in most samples of malignant cervix and a small minority of normal cervix samples. Compared with the isomorphic distribution of lactate dehydrogenase enzymes in normal uterine tissue, cancers showed a shift towards either a more anodal or a more cathodal pattern. The former may be associated with tumours enjoying a good oxygen supply, and the latter with tumours which, because of their depth or poor blood supply have to function under less aerobic conditions.

Electrophoresis, Polyacrylamide Gel↗