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Biomedical subjects

T D Phillips

Publications and source records attributed to T D Phillips.

119 records · Page 7Linked to original sources
PubMed1978

Effects of patulin on the kinetics of substrate and cationic ligand activation of adenosine triphosphatase in mouse brain.

Patulin (4-hydroxy-4H-furo[3,2-c]pyran-2(6H)-one), a carcinogenic lactone produced as a major metabolite by several fungi, inhibited the Mg++-dependent Na+-K+ activated adenosine triphosphatase (ATPase) activity of mouse brain microsomal fractions with an estimated IC50 of 3.0 X 10(-4) M. Inhibition was concentration dependent. Hydrolysis of ATP was linear with both time and enzyme concentration either with or without patulin in reaction mixtures. Altered pH and activity curves for Na+-K+ ATPase demonstrated comparable inhibition by patulin in buffered acidic ranges through an optimum of 7.5, followed by a reduction of toxicity to this system at higher alkaline pH. Kinetic studies of cationic-substrate activation of Na+-K+ ATPase indicated noncompetitive inhibition with respect to ATP (at low affinity nucleotide-directed sites) and Na+ (in the presence of low, noninterfering concentrations of K+). Competitive inhibition with respect to activation of the Na+-k+-stimulated activity and K+-stimulated p-nitrophenyl phosphatase activity of the enzyme system was indicated by altered binding site parameters without change in apparent Vmax in the presence of patulin. Activity was partially restored by washing. Preincubation of patulin with dithiothreitol or glutathione protected the enzyme from inhibition. Results suggest that patulin exerted its effect on Na+-K+ ATPase either directly by interfering with K+ binding or indirectly by inducing a conformational change in the enzyme.

4-Nitrophenylphosphatase↗
PubMedDate not supplied

The effects of ochratoxin A on postimplantation rat embryos in culture.

The mycotoxin, ochratoxin A (OA), is a potent in vivo teratogen. Studies were performed to determine the in vitro effects of OA on postimplantation rat embryos. Embryos were explanted from pregnant Sprague-Dawley rats on day 10 of gestation and were cultured (within the yolk sac) for 45 hr in gassed rat serum containing OA at concentrations between 0 and 300 micrograms/mL. Gross morphology, histopathology and protein and DNA content of embryos were evaluated. An OA concentration-dependent reduction in yolk sac diameter, crown-rump length, somite number count, and protein and DNA content was observed. Ochratoxin A treatment also resulted in an increase in the incidence of defective embryos. Malformations included: growth retardation, hypoplasia of the telencephalon, poor flexion, stunted limb bud development, underdeveloped sensory primordia and decreased mandibular and maxillary size. Histological examination demonstrated extensive OA-induced necrosis of embryonal mesodermal structures and neuroectoderm. Thus, the rat embryo in culture is a sensitive indicator of OA toxicity and may be useful for predicting developmental hazards associated with this mycotoxin.

Animals↗
PubMedDate not supplied

Inhibition of 3,3',4,4',5-pentachlorobiphenyl-induced fetal cleft palate and immunotoxicity in C57BL/6 mice by 2,2',4,4',5,5'-hexachlorobiphenyl.

3,3',4,4',5-Pentachlorobiphenyl (pentaCB) caused a dose-dependent induction of fetal cleft palate in offspring from pregnant C57BL/6 mice exposed to a single dose (783 or 1044 micrograms/kg) of this compound on gestation day 10. In contrast, 2,2',4,4',5,5'-hexaCB did not cause cleft palate at a dose of 271 mg/kg and, in pregnant mice cotreated with 2,2',4,4',5,5'-hexaCB (271 mg/kg) plus 783 or 1044 micrograms/kg 3,3',4,4',5-pentaCB, fetal cleft palate formation was significantly inhibited. 3,3',4,4',5-PentaCB (6 micrograms/kg) also inhibited the splenic plaque-forming cell (PFC) response and serum IgM levels in C57BL/6 mice treated with the T cell-independent antigen trinitrophenyl-lipopolysaccharide. At doses as high as 72 mg/kg, 2,2',4,4'-5,5'-hexaCB was not immunotoxic; however, in mice cotreated with a immunotoxic dose of 3,3',4,4',5-pentaCB plus different doses of 2,2',4,4',5,5'-hexaCB (18, 36 and 72 mg/kg), there was a dose-dependent inhibition of 3,3',4,4',5-pentaCB-induced immunotoxicity. These non-additive (antagonistic) interactions of prototypical polychlorinated biphenyl (PCB) congeners may be an important consideration in development of a toxic equivalency factor approach for hazard and risk assessment of PCB mixtures.

Animals↗
PubMedDate not supplied

Effects of the mycotoxins citrinin and ochratoxin a on hepatic mixed-function oxidase and adenosinetriphosphatase in neonatal rats.

The effects of citrinin, ochratoxin A, or a combination of the two mycotoxins on the hepatic monooxygenase system and on hepatic and renal adenosinetriphosphatase (ATPase) activities were examined in neonatal rats exposed to a single treatment of one or both toxins. Animals received (po) 25 mg/kg citrinin, 1 mg/kg ochratoxin A, or 25 mg/kg citrinin plus 1 mg/kg ochratoxin A within 24 h of birth. Pups were killed 12 d later. Citrinin or ochratoxin A alone did not affect hepatic ATPase. Renal oligomycin-sensitive Mg2+-ATPase was inhibited to the same degree by ochratoxin A and the combination treatment. A synergistic effect of the two mycotoxins was observed on renal Na+-K+-ATPase. Significant effects, due to the mycotoxin interaction, were also observed on cytochrome P-450 content, NADPH-dependent dehydrogenase, and NADPH-cytochrome c reductase.

Adenosine Triphosphatases↗
PubMedDate not supplied

Structural modification of polyfunctional rubratoxin B: effects on mammalian adenosine triphosphatase.

Rubratoxin B, an alpha, beta unsaturated lactone containing bisanhydride metabolite of certain toxigenic strains of penicillium molds, significantly inhibited in vitro brain microsomal Na+ - K+ adenosine triphosphatase from swine, mouse, and rat with IC50's of 6.76, 6.67, and 6.80 x 10(-6) M, respectively. Mitochondrial Mg++ oligomycin-sensitive ATPase from mouse liver was also inhibited with an IC50 of 6.30 x 10(-6) M rubratoxin B. Structural modification of the polyfunctional parent compound (rubratoxin B) to rubratoxin A (a gamma lactol replaces one of the anhydride moieties) or formation of the dihydro analogs of rubratoxins A and B (2,3 saturated delta lactone) decreased inhibition to all ATPase systems. The structure-activity relationship relative to ATPase inhibition was rubratoxin B greater than dihydrorubratoxin B greater than rubratoxin A greater than dihydrorubratoxin A. The order of reactivity by these analogs to brain microsomal Na+ -K+ ATPase from 3 mammalian species and to mouse hepatic mitochondrial Mg++ ATPase was similar, indicating no significant species variations. These results suggest that the previously demonstrated in vivo inhibition of adenosine triphosphatase preparations by rubratoxin B was the result of the intact parent compound, because chemical alteration of any one of the functional moieties (either the maleic anhydride ring or conjugated lactone) resulted in significantly decreased inhibition of ATPase activity.

Adenosine Triphosphatases↗
PubMedDate not supplied

Immunologic effects of low levels of ochratoxin A in ovo: utilization of a chicken embryo model.

Ochratoxin A (OA) was administered to 13-day-old chicken embryos via the chorioallantoic membrane. The 7-day LD50 value (day 20 incubation) of OA was calculated at 7.9 micrograms of OA. Ochratoxin-treated embryos (2.5 micrograms) had slight but significant changes in numbers of immunoglobulin-bearing cells in the bursa but not in the spleen. Chicks hatched from in ovo-treated eggs were challenged with 9 X 10(4) colony-forming units (CFU) of beta-hemolytic Escherichia coli (O1:K1) at 7 days of age via the thoracic air sac. Lesion scores of OA-treated chicks were equal to or less severe than those of controls. Hatchmates of the above chicks were vaccinated with a homologous killed E. coli bacterin (O1:K1) at both 2 and 4 weeks of age and challenged with 10(4) CFU of E. coli at 7 weeks. Post-challenge lesions were present in three vaccinated untreated controls and no OA-treated chicks. We conclude that although in ovo exposure to OA may marginally suppress immunoglobulin-bearing cells of bursa, chicks hatched from OA-treated eggs respond as well as controls to an antigen and resist infection by a virulent organism.

Animals↗
PubMedDate not supplied

Efficacy of zeolitic ore compounds on the toxicity of aflatoxin to growing broiler chickens.

Commercially available zeolitic ore compounds, when incorporated into the diets at 0.5%, were evaluated for their ability to reduce the deleterious effects of 3.5 mg aflatoxin/kg feed on growing broiler chickens from 1 day to 3 weeks of age. In a series of four experiments, the compounds used included the following: mordenite (particle size of -20 mesh; Zeomite); clinoptilolite (particle size of -20 mesh; Zeobrite); SC Zeolite (particle size of -20 mesh); and clinoptilolite (particle size of -35 mesh; Clino 1) or clinoptilolite (particle sizes of -20 plus +35 mesh; Clino 2). Results demonstrated that 0.5% Zeobrite, Clino 1, or Clino 2 added to aflatoxin-contaminated diets did not significantly (P < 0.05) diminish the toxicity of high concentrations of aflatoxin to growing broiler chicks. Zeomite mordenite ore reduced the toxicity of aflatoxin to growing chicks by 41%, as indicated by weight gains, liver weight, and serum biochemical measurements, which compares favorably with its in vitro binding capacity to aflatoxin. SC Zeolite reduced weight-gain toxicity of aflatoxin by approximately 29%.

Adsorption↗