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Biomedical subjects

M R Boyd

Publications and source records attributed to M R Boyd.

At least 289 records · Page 16Linked to original sources
PubMed1978

Paradoxical effects of cobaltous chloride and salts of other divalent metals on tissue levels of reduced glutathione and microsomal mixed-function oxidase components.

Treatment of animals with cobaltous chloride caused decreases in hepatic, pulmonary and renal cytochrome P-450, and alterations in levels of other components of microsomal mixed-function oxidases, which can alter the rate of biotransformation of certain drug substrates. The treatment also caused a striking, dose-dependent elevation in tissue levels of reduced glutathione (GSH), within 2 to 8 hours. The effect of cobalt on GSH occurred in all tested animal species and strains. Actinomycin-D partially prevented the cobalt-stimulated rise in hepatic GSH. Salts of several other divalent metals also produced sharply elevated levels of hepatic GSH, occurring concomitantly with decreased microsomal content of cytochrome P-450. These results suggest that pretreatment of animals with cobaltous chloride, or other divalent metal salts, could alter the disposition of certain toxic, alkylating drug metabolites not only by decreasing the rate of formation of the reactive metabolites, but also by increasing the amount of GSH available for the formation of their less reactive, less toxic, GSH conjugates.

Animals↗
PubMed1976

Role of metabolic activation in the pathogenesis of chemically induced pulmonary disease: mechanism of action of the lung-toxic furan, 4-ipomeanol.

Many xenobiotics produce hepatic injury due to their metabolism in the liver to highly reactive electrophile intermediates which form covalent conjugates with nucleophilic cellular constituents. This presentation describes studies indicating that the production of chemically reactive metabolites by pulmonary metabolism of xenobiotics can also play a fundamental role in the pathogenesis of chemically induced lung disease.

Animals↗
PubMedDate not supplied

Metabolic activation as a basis for organ-selective toxicity.

Historically, the concept of metabolic activation was first forwarded to explain the in vivo activity of certain carcinogenic chemicals that without prior metabolism were chemically inert and biologically inactive. Subsequently, the concept has been extended to explain the effects of many different classes of chemicals causing diverse toxicities. Because of its major role in drug metabolism, the liver is a prominent site for toxic injury by agents requiring metabolic activation. The liver can also be the source of reactive metabolites that damage extrahepatic organs. But, organ selective toxicity can also result from the in situ metabolic activation of foreign chemicals in extrahepatic target tissues such as the lungs and the kidneys. Moreover, extrahepatic tissues generally are much more heterogeneous in cellular composition compared to the liver, and the localization of drug metabolizing enzymes in certain cell populations may result in highly cell selective toxic injury. The significance of metabolic activation and toxicity--and the importance of the particular chemical structure of individual compounds, as well as host factors such as species, age, sex, and pretreatment effects--on target-organ-selective toxicity by reactive metabolites are illustrated by studies with various furan derivatives, an important class of environmental chemicals.

Animals↗
PubMedDate not supplied

Antineoplastic agents 460. Synthesis of combretastatin A-2 prodrugs.

The original synthesis of combretastatin A-2 (1a) was modified to provide an efficient scale-up procedure for obtaining this antineoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by phosphorylation employing in situ formation of dibenzylchlorophosphite followed by cleavage of the benzyl ester protective groups with bromotrimethylsilane to afford the phosphoric acid intermediate 11. The latter was immediately treated with sodium methoxide to complete a practical route to the disodium phosphate prodrug (2a). The phosphoric acid precursor (11) of phosphate 2a was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts (2a-q) was evaluated with respect to relative solubility behavior, cancer cell growth inhibition and antimicrobial activity.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Morphological and immunocytochemical characteristics of human tumor cell lines for use in a disease-oriented anticancer drug screen.

A panel of 60 human tumor cell lines is currently being used in the U.S. National Cancer Institute's in vitro anticancer drug screen. The panel is organized into 7 subpanels; 6 leukemia/lymphoma lines comprise one subpanel, and 54 other lines are organized into subpanels representing solid tumors of the central nervous system (CNS), colon, lung, ovaries, kidneys and melanomas. In the present study, the leukemia and lymphoma cell lines were analyzed by flow cytometry for appropriate CD antigens; all but 1 line showed patterns of expression consistent with their reported derivations. The solid tumor lines were characterized individually using morphological and immunocytochemical techniques to determine their relative degrees of representativity for the subpanels within which they are currently grouped. Histological, histochemical and ultrastructural examinations were performed on cell lines grown under identical conventional culture conditions and as xenografts in nude mice. Immunocytochemistry using panels of antibodies raised against 6 types of intermediate filaments, 7 adenocarcinoma-associated antigens, 7 melanoma/neuro-ectodermal-associated antigens, 3 neuroendocrine-associated antigens, 9 urinary tract associated antigens, and 4 markers of muscle differentiation was done on cells grown in monolayer culture. Central nervous system (CNS) cell lines lacked expression of glial fibrillary acidic protein, but all had other features consistent with derivation from glioblastoma. Lines derived from adenocarcinomas of the colon, lung and ovary, for the most part, expressed adenocarcinoma-associated antigens and showed histological and/or ultrastructural evidence of gland formation and other adenomatous features. Most of these lines were poorly differentiated. Lines derived from large-cell and squamous-cell cancers also showed some characteristics consistent with their reported origins, except for one line which showed immunocytochemical and morphologic characteristics consistent with rhabdomyosarcoma. The 2 lines derived from small cell lung cancer (SCLC) lacked neurosecretory granules and 3 other SCLC markers but showed morphologic features consistent with SCLC. Most melanoma cell lines strongly expressed melanoma-associated antigens and were morphologically similar to human melanoma. Five lines produced premelanosomes, melanosomes or melanin. Most of the renal cancer cell lines showed morphologic or immunocytochemical features consistent with renal clear cell carcinoma. Collectively, these morphological and immunocytochemical analyses provide information concerning tissue of origin, tumor type, degree of differentiation and other biologic features essential to the use of these lines in a disease-oriented in vitro antitumor drug screen and to the interpretation of data derived therefrom.

Antibody Specificity↗
PubMedDate not supplied

Metabolism of 2-acetylaminofluorene in isolated rabbit pulmonary cells. Evidence for the heterogeneous distribution of monooxygenase activity in lung tissue.

The regiospecific hydroxylation of 2-acetylaminofluorene (2-AAF) has been used to monitor monooxygenase activity in isolated rabbit lung cells. Following isolation, the cells were separated into seven different fractions according to size by centrifugal elutriation. Macrophages were recovered from the lungs by lavage and examined in parallel with the parenchymal cell populations. The resulting fractions were assayed for 2-AAF hydroxylase activity and were examined for the presence of endothelial cells (angiotensin-converting enzyme), alveolar type II cells (modified Papanicolaou stain), polymorphonuclear leukocytes (modified Papanicolaou stain), bronchiolar Clara cells (nitro blue tetrazolium stain), and ciliated cells (phase contrast microscopy). Highest hydroxylase activities were seen in the cell fraction containing the largest percentage of Clara cells. The activity profiles provided evidence for a population of cells not correlating with either alveolar type II cells or Clara cells possessing substantial monooxygenase activity. The alveolar macrophage almost exclusively hydroxylated 2-AAF in the 9-position and the cell fraction containing the higher percentage of endothelial cells metabolized 2-AAF the least. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin preferentially induced the 7-hydroxylation of 2-AAF and either did not alter or decreased the rate of formation of the other hydroxy metabolites. An exception was seen in fraction 1 where 2,3,7,8-tetrachlorodibenzo-p-dioxin induced the hydroxylation of 2-AAF to all products except 3-hydroxy-AAF. Evidence is presented for the presence of a cell type(s) not identifiable as either the Clara or alveolar type II cell with considerable monooxygenase activity.

2-Acetylaminofluorene↗
PubMedDate not supplied

Effects of vitamin E on the distribution and metabolism of nitrofurantoin in rats.

Previous studies have shown a significant increase in the pulmonary toxicity of nitrofurantoin (NF) in animals fed a diet lacking vitamin E. The authors have therefore examined the pharmacokinetics of NF in control and vitamin E-deficient male Sprague-Dawley rats. NF was rapidly absorbed following subcutaneous injection and was cleared from all tissues examined (blood, lung, liver and kidney) in a biphasic manner. Substantial metabolism of the drug was observed, and the disposition of NF metabolites was qualitatively similar to that of the parent compound. The most apparent difference between control and vitamin E-deficient animals was a significant increase in tissue metabolite levels 4-16 hr after treatment. Unchanged NF was also elevated in all tissues examined 16 hr after treatment in the vitamin E-deficient animals. Urinary excretion of NF and metabolites accounted for 68% of the total dose in control rats and 35% in vitamin E-deficient rats. This study illustrates a marked alteration in NF disposition in animals fed a diet lacking vitamin E when compared with controls. The observed alterations appear to be related to a decreased renal clearance of both NF and metabolites.

Animals↗
PubMedDate not supplied

Ipomeanol 4-glucuronide, a major urinary metabolite of 4-ipomeanol in the rat.

Urinary excretion and metabolism of 4-ipomeanol was studied in rats injected ip with the radiolabeled compound. There was a rapid elimination of radioactivity in the urine, amounting to 47% of the administrated dose within 4hr. One major metabolite was isolated and purified by HPLC. Analysis by analytical HPLC, beta-glucuronidase hydrolysis, and mass spectrometry identified this material as ipo-meanol 4-glucuronide. The large amount of this metabolite excreted suggests that 4-glucuronidation is an important detoxication reaction in vivo for 4-ipomeanol in rats.

Animals↗