PubMed Health⌕ Search

Biomedical subjects

D G Graham

Publications and source records attributed to D G Graham.

At least 109 records · Page 6Linked to original sources
PubMed1979

Delayed neurotoxic, late acute and cholinergic effects of S,S,S-tributyl phosphorotrithioate (DEF): subchronic (90 days) administration in hens.

Subchdronic administration of S,S,S-tributyl phosphorotrithioate (DEF) caused 3 toxicologic effects in hens, depending upon route of administration. Small delay oral doses (0.5--20 mg/kg) of DEF produced ataxia, which progressed to paralysis and death in some birds. Large daily oral doses (40 and 80 mg/kg) caused a 'late acute' effect 4 days after administration. The clinical signs of the late acute effect were identical to those produced by n-butyl mercaptan (nBM), a hydrolytic product of DEF, and were not relieved by atropine sulfate. The late acute effect of DEF overlapped with the clinical signs of delayed neurotoxicity. These hens died early, and while one hen showed histopathological lesions in peripheral nerves, another showed unequivocal lesions in the central nervous system. Topical application of daily doses of DEF consistently produced delayed neurotoxicity in the absence of late acute poisonining and was characterized by degeneration of the central and peripheral nerve tissues. Orally administered DEF was rapidly metabolized in the gastrointestinal tract to nBM, which apparently caused the late acute toxic effect. Topically administered DEF, which was not subjected to gastrointestinal tract hydrolysis, caused delayed neurotoxicity but did not produce a late acute effect.

Animals↗
PubMed1979

Delayed neurotoxicity of subchronic oral administration of leptophos to hens: recovery during four months after exposure.

Daily oral administration of small doses of technical grade O-methyl O-4-bromo-2,5-dichlorophenyl phenylphosphonothioate (leptophos, 0.5-20.0 mg/kg) caused delayed neurotoxicity in hens. Severity of clinical condition and progression or improvement of signs of delayed neurotoxicity depended on the dose and duration of administration. Hens given 20.0 mg/kg suffered ataxia, paralysis, and death. Intermediate doses (5 and 10 mg/kg) caused ataxia, with most treated hens showing no change in clinical condition during the 4-mo observation period. Hens given small doses (2.5 and 1.0 mg/kg) demonstrated regression of neurological deficits after administration of leptophos was stopped. Hens given the smallest tested dose (,.5 mg/kg) developed mild ataxia and showed total recovery during the observation period. Days of administration and total administered dose before onset of ataxia depended on the daily dose. Degeneration of axons and myelin i, the spinal cord was the most consistent histopathologic change and was identical to that observed in tri-o-cresyl phosphate (TOCP) control hens. Only one hen, which died early in the treatment period, showed peripheral nerve degeneration. Controls consisted of 3 groups of hens given a daily oral dose of 10.0 mg/kg TOCP, 1.0 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion), or an empty gelatin capsule. TOCP-treated hens developed delayed neurotoxicity, whereas those given parathion showed initial leg weakness but subsequently recovery without developing delayed neurotoxicity. Controls given gelatin capsules remained normal.

Animals↗
PubMed1979

On the origin and significance of neuromelanin.

The amount of cytoplasm within catecholamine neurons occupied by neuromelanin was found to increase progressively with the patient's age. The accretion of neuromelanin was accompanied by an expansion of the cytoplasm of neurons in the substantia nigra and locus ceruleus. These observations support the concept that neuromelanin is a waste product of catecholamine metabolism, derived from the oxidation of dopamine, nonrepinephrine, and related compounds to quinones. The existence of oxidative pathways for catecholamines suggests that defects in their compartmentalization, transport, or degradation may present the cell with sufficient levels of cytotoxic quinones and free radical species to result in the degeneration of neurons observed in Parkinson's disease.

Adult↗
PubMed1978

The toxicity of melanin precursors.

The quinone intermediates resulting from tyrosinase-mediated oxidation of tyrosine were evaluated as sulfhydryl reagent inhibitors of purified calf thymus DNA polymerase alpha in order to determine which of these might be cytotoxic. Dopachrome and an oxidation product of 2,4,5-trihydroxyphenylalanine were relatively ineffective as inhibitors of DNA polymerase alpha. On the other hand, a dopaquinone analogue, 4-(2-N-acetylaminoethyl)-1,2-benzoquinone, synthesized from N-acetyl dopamine, was demonstrated to have marked affinity for this sulfhydryl enzyme. This property was shared by 1,2-benzoquinone. These studies point to dopaquinone as a significant toxic metabolite in melanin biosynthesis.

Animals↗
PubMed1978

Hemorrhagic cerebral white matter: infarction with cerebral deep venous thrombosis and hypoxia.

Postmortem examination of the brain of a 5-week-old boy disclosed extensive thrombosis of the deep venous system and widespread necrosis of the cerebral parenchyma. As is characteristic of this uncommon form of cerebrovascular disease, malacia was present in the central gray matter but was only focal and incospicuous in contrast to a diffuse hemorrhagic softening of the centrum semiovale. This association of deep venous thrombosis and predominant white matter necrosis suggests that impairment of venous drainage should be considered in the pathogenesis of certain disorders of the cerebral white matter.

Aspergillosis↗
PubMed1977

The role of 2,4,5-trihydroxyphenylalanine in melanin biosynthesis.

Both 3,4-dihydroxyphenylalanine and 2,4,5-trihydroxyphenylalanine were oxidized with periodate and mushroom tyrosinase to determine whether the latter compound is an intermediate in melanin biosynthesis. Matrix analysis of the spectra obtained with a rapid scan spectrophotometer and comparison of the spectra of quinone intermediates with model quinones disclosed that, although 2,4,5-trihydroxyphenylalanine can be oxidized to 2-carboxy-2,3-dihydroindole-5,6-quinone (dopachrome), this oxidation proceeds through a stable intermediate, 5-(2-carboxy-2-aminoethyl)-2-hydroxy-1,4-benzoquinone, which does not appear in the oxidation of 3,4-dihydroxyphenylalanine to dopachrome. Thus, these studies are in agreement with the original postulate, that 4-(2-carboxy-2-aminoethyl)-1,2-benzoquinone and leukodopachrome are the intermediates in the major pathway for dopachrome synthesis.

Basidiomycota↗
PubMed1977

gamma-L-Glutaminyl-4-hydroxybenzene, an inducer of cryptobiosis in Agaricus bisporus and a source of specific metabolic inhibitors for melanogenic cells.

A stable phenol, gamma-L-glutaminyl-4-hydroxybenzene (GHB), is oxidized by tyrosinase in the gill tissues of the mushroom Agaricus bisporus to a quinone and a second oxidation product which together suppress mitochondrial energy production and the synthesis of proteins and nucleic acids in the zygote, thus establishing dormancy in the spores. Brief incubation of cultured murine L1210 leukemia and B-16 melanoma cells with muM concentrations of the purified quinone notably prolonged survival times or blocked tumor growth in histocompatible mice inoculated i.p. with high concentrations of the exposed cells. The instability of the quinone precluded in vivo administration. The short incubation of cultured B-16 melanoma cells with mM concentrations of GHB markedly prolonged survival times or abolished tumor growth in histocompatible C57BL/6J mice inoculated i.p. with 5 X 10(6) exposed cells. This response did not occur with L1210 leukemia cells, which lack the enzyme tyrosinase. The survival times of mice bearing B-16 melanoma, but not of those with L1210 leukemia, were slightly prolonged by a single injection and were significantly extended by daily i.p. injections of GHB. Normal C57BL/6J mice, given GHB i.p. as single or multiple 400-mg/kg doses, manifested no systemic toxicity but showed depigmentation of the hair after 2 to 3 weeks. These studies provide evidence that GHB exerts cytotoxicity specifically for cells that by their content of tyrosinase convert the phenol to the quinone. This targeted response minimizes systemic toxocity and underscores the potential therapeutic application of this agent to melanocarcinoma.

Agaricales↗
PubMed1977

Inhibition of DNA polymerase from L1210 murine leukemia by a sulfhydryl reagent from agaricus bisporus.

The 490 quinone, a natural sulfhydryl-arylating reagent from the mushroom, Agaricus bisporus, markedly inhibited L1210 murine leukemia DNA polymerase alpha while resulting in little inhibition of DNA polymerase beta from this source. This quinone was more strongly inhibitory than p-chloromercuri-benzoate or N-ethylmaleimide and was less readily neutralized by sulfhydryl-containing molecules such as dithioerythritol. Preliminary experiments indicate that DNA protects DNA polymerase alpha from inhibition by the 490 quinone. The inhibition of DNA synthesis by quinone 490 may contribute significantly to the cytotoxicity of this compound and to the potential of gamma-L-glutaminyl-4-hydroxybenzene as an antitumor agent.

Animals↗
PubMed1975

Concerning the role of mitochondria in cryptobiosis.

The metabolic characteristics of the mitochondria of Agaricus bisporus are altered in the zygote by specific inhibitors that permit them to retain structural integrity in the dormant spore and enable them to initiate energy production, with apparent protein synthesis and replication during the initial phase of germination. The insensitivity of the earliest events of germination to selective cytoplasmic and nuclear inhibitors characterizes this as a transient period of unusual mitochondrial autonomy. To define the intrinsic metabolic potentials of the organelle and its role in cryptobiosis, mitochondria were fractionated aseptically from presporulating zygotes and were placed in dialysis chambers surrounded by nutrient media at 15 C. For periods through 48 hours, the isolated mitochondria manifested the capacity to incorporate labeled amino acids linearly into proteins and retained stable electrophoretic protein profiles for more than 5 days. They maintained fine structural integrity for at least 10 days, some developed septational membranes, and they increased numerically. These metabolic activities were dependent upon a nutrient substrate.

Amino Acids↗
PubMed1975

Cytostatic, cytocidal and potential antitumor properties of a class of quinoid compounds, initiators of the dormant state in the spores of Agaricus bisporus.

Evidence indicates that dormancy is initiated in the spores of Agaricus bisporus by two quinoid compounds that appear in the zygote during the prodromal period of sporulation. Both are derivatives of a phenol, gamma-L-glutaminyl-4-hydroxybenzene. When purified, these quinoids specifically inhibit mitochondrial respiratory enzymes and protein synthesis in the mushroom and have comparable effects with rat liver mitochondria and ribosomes, with intact bacteria, and with bacterial ribosomes and RNA polymerase in vitro. Five species of mouse ascites tumor cells showed prompt and marked inhibitions of nucleic acid and protein synthesis when millimolar concentrations of these quinoids were added to the tissue culture medium of the tumor cells. Only a small percentage of the cells was killed immediately, as judged by trypan blue uptake. When large numbers of exposed BP8 sarcoma and EL4 leukemic cells were reinjected intraperitoneally into histocompatible mice, the survival times of these animals were notably prolonged beyond those of animals injected with tumor cells that had not been exposed to these inhibitors. In a dose-dependent manner, increasing concentrations of inhibitors produced proportionate increments in survival time, while higher concentrations totally abolished tumor cell growth. The findings indicate that these simple quinoid compounds, which initiate the dormant state in spores, produce a cytostatic state in mammalian tumor cells and thus potentially have strong antitumor properties (Am J Pathol 78:33-48, 1975).

Amino Acids↗
PubMed1974

Bacteriocidal properties of a class of quinoid compounds related to sporulation in the mushroom, Agaricus bisporus.

A small phenolic compound, gamma-L-glutamyl-4-hydroxybenzene, and several quinoid derivatives appear in the gill tissues of the mushroom, Agaricus bisporus, during the prodromal period of sporulation. These quinoids markedly inhibit respiratory enzymes and protein synthesis. The temporal relationship of their appearance to sporulaton and their properties as metabolic inhibitors indicate that they initiate and maintain the dormant or cryptobiotic state of the spore. In very low concentrations, these quinoids show significant bacteriocidal action against a variety of microorganisms. The therapeutic potential of these antibiotic properties is considered.

Anti-Bacterial Agents↗