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Biomedical subjects

H A Milman

Publications and source records attributed to H A Milman.

31 records · Page 2Linked to original sources
PubMed1976

Inhibition of L-asparagine synthetase by mucochloric and mucobromic acids.

Mucochloric and mucobromic acids are powerful inhibitors of tumoral and pancreatic L-asparagine synthetases. Two nitrogen donors, L-glutamine and ammonia, can be used by these enzymes; at a concentration of 1 mmol/l, mucochloric and mucobromic acids preferentially inhibit the utilization of ammonia as opposed to L-glutamine in vitro. Using the tumoral enzyme, kinetic analysis revealed that mucochloric acid produced inhibition which was apparently noncompetitive with ammonia but competitive with L-glutamine. In molar excess, L-glutamine and dithiothreitol effectively antagonized such inhibition; dialysis, however, failed to reverse established inhibition. These findings, suggest that the drugs operate by covalent attachment to crucial sulfhydryl functions on the enzyme.

Ammonium Chloride↗
PubMed1976

Inhibitors of L-asparagine synthetase, in vitro.

A systematic search has been made for inhibitors of L-asparagine synthetase (L-glutamine hydrolyzing, EC 6.3.5.4) from leukemia 5178Y/AR, a rodent neoplasm resistant to the oncolytic enzyme L-asparaginase (EC 3.5.1.1), The classes of chemicals examined in this search included substrate and product analogs, agents capable of reacting with sulfhydryl functions, and a variety of modifiers whose mechanism of interaction with proteins is known. In general, antagonists of L-glutamine and thiol reagents proved to be the most effective inhibitors of L-asparagine synthetase from this tumor source. Within these groups, certain structural prerequisites to inhibition are reported. Attempts to correlate oncolytic potency with enzyme-inhibitory potency were unsuccesful.

Adenosine Triphosphate↗
PubMed1974

The distribution of L-asparagine synthetase in the principal organs of several mammalian and avian species.

A survey was conducted of the distribution of l-asparagine synthetase and of l-asparaginase in the principal organs of representative mammals and birds. Although a radiometric assay was used as a routine, several additional criteria, including enzymic and chromatographic ones, were used to verify that the product of the synthetase was l-asparagine. Recoveries of exogenous l-asparagine were assessed in the presence of a number of mouse organs and found to be about 85%. In addition, evidence is presented for the existence in mouse liver of a thermolabile activity capable of destroying l-asparagine and stimulated by high concentrations of NH(4) (+) ions. Of the organs surveyed, pancreas was generally found to synthesize l-asparagine at the most rapid rate, whereas extracts of liver catalysed the decomposition of this amide at the greatest velocity. Of the species studied, guinea pig had the highest activities of pancreatic l-asparagine synthetase and also of hepatic l-asparaginase. The pancreas of mouse and ox also were good sources of l-asparagine synthetase.

Amino Acids↗
PubMed1972

A radiometric technique for measuring L-asparagine in picomole quantities.

A radiometric technique for measuring l-asparagine in small samples of biological origin is presented. After removal of l-glutamate and l-aspartate by enzymic decarboxylation, l-asparagine in the sample is hydrolysed to l-aspartate with l-asparaginase from Escherichia coli. The l-aspartate so generated is then enzymically transaminated with 2-oxo[1-(14)C]glutarate yielding l-[1-(14)C]glutamate. After specific chemical removal of unchanged 2-oxo[1-(14)C]glutarate, the l-[1-(14)C]glutamate generated is determined by scintillation counting of the radioactivity. This technique can measure the concentration of l-asparagine present in approx. 1mul of mouse blood, and is capable of detecting as little as 25pmol of the amide. Illustrative applications of the method are presented and discussed, including measurement of the l-asparagine content of the mouse hypophysis.

Animals↗
PubMedDate not supplied

Pancreatic carcinogenesis and naturally occurring pancreatic neoplasms of rats and mice in the NCI carcinogenesis testing program.

Over two hundred chemicals were examined in a two year rodent bioassay system for possible carcinogenicity. Of these, only nitrofen significantly increased the incidence of neoplasms of the exocrine pancreas of rats or mice (female Osborne-Mendel rats); azinphosmethyl was the only agent tested which significantly increased the incidence of islet-cell tumors of rats or mice (male Osborne-Mendel rats). The use of the rat (Osborne-Mendel or Fischer 344) and mouse (B6C3F1) as models for the detection of chemically-induced pancreatic neoplasms also was investigated. The incidences of specific neoplasms of the exocrine or endocrine pancreas produced by all chemicals tested were combined and compared with the combined incidences of similar neoplasms in control animals in order to increase the sensitivity of the test. The data obtained through this procedure suggests that the male rat may be a good, sensitive model for the detection of islet-cell tumors.

Animals↗