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Biomedical subjects

R A Neal

Publications and source records attributed to R A Neal.

At least 55 records · Page 3Linked to original sources
PubMed1982

The efficacy of a novel compound, (e)-1-(4'-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene against Trypanosoma cruzi in mice.

The biological properties of a novel compound 353C with high activity against Trypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C has a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.

Animals↗
PubMed1982

Toxicology of thiono-sulfur compounds.

Thiono-sulfur-containing compounds cause a wide variety of toxic effects in mammals. These toxic effects of thiono-sulfur-containing compounds appear to be at least partially the result of their metabolism to reactive intermediates by the cytochrome P-450-containing monooxygenase enzyme systems. Covalent binding of (atomic) sulfur released in the cytochrome P-450 monooxygenase catalyzed metabolism of certain thiono-sulfur compounds appears to be responsible for the inhibition of monooxygenase activity and the loss of cytochrome P-450 seen on administration of these thiono-sulfur compounds in vivo or incubation with cytochrome P-450 monooxygenase enzymes in vitro. Liver necrosis and perhaps the induction of lung edema and neoplasia as well as other effects of thiono-sulfur-containing compounds are more likely the result of the covalent binding of the electrophilic S-oxides or S-dioxides or carbene derivatives of these S-oxides and S-dioxides to tissue macromolecules. The rationale for implicating metabolites of thiono-sulfur compounds other than atomic sulfur in these effects derives from the experiments with thioacetamide and the fact that atomic sulfur is highly reactive and appears to bind predominantly or exclusively to cytochrome P-450. It is difficult to rationalize why binding to and inhibition of cytochrome P-450 would lead to the production of, for examples, liver necrosis.

Animals↗
PubMed1982

Inhibition of rat liver cytochrome P-450 by benzyl hydrodisulfide.

The inhibition of rat liver microsomal cytochrome P-450 by benzyl hydrodisulfide has been examined as a model system for the inactivation of cytochrome P-450 seen during the microsomal metabolism of thiono-sulfur-containing compounds. Benzyl hydrodisulfide decreased enzymatic activity toward benzphetamine when incubated with hepatic microsomes prior to the assay for monooxygenase activity. In addition, incubation of microsomes with the hydrodisulfide caused a decrease in the level of cytochrome P-450 detectable as its carbon monoxide complex as well as a decrease in heme detectable as its pyridine-hemochromogen. In a typical experiment, the loss of enzymatic activity, cytochrome P-450, and heme were 65, 56, and 51%, respectively. These data suggest that the major loss of monooxygenase activity and of cytochrome P-450 which was seen on incubation of microsomes with benzyl hydrodisulfide results from an alteration in the structure of the heme moiety of cytochrome P-450. A similar alteration in the heme moiety of cytochrome P-450 is believed to be responsible, in part, for the loss of monooxygenase activity and cytochrome P-450 seen on incubation of parathion and other thiono-sulfur-containing compounds with hepatic microsomes or a reconstituted cytochrome P-450-containing monooxygenase system.

Animals↗
PubMed1982

Dinitrophenol poisoning: a diagnosis to consider in undiagnosed fever.

A 32-year-old farmer had signs and symptoms of dinitrophenol poisoning after crop spraying with a herbicide containing derivatives of 2,4-dinitrophenol. Dinitrophenol causes toxicity by the uncoupling of oxidative phosphorylation in the mitochondria of cells throughout the body. In man the classic syndrome consists of lassitude, malaise, headache, increased perspiration, thirst, and dyspnea which may progress to hyperpyrexia, profound weight loss, respiratory failure, and death. Because dinitrophenol compounds are widely used, it is likely that some patients with unexplained fever have unrecognized dinitrophenol poisoning. Prompt recognition of the clinical manifestations of toxicity is vital for appropriate therapy. We describe a method for detection of dinitrophenol in plasma and urine.

Adult↗
PubMed1982

Rat liver microsomal metabolism of propyl halides.

The in vitro metabolism of 1-propyl halides (chloride, bromide, and iodide) by hepatic microsomes from phenobarbital-induced rats was examined. The following metabolites were detected: propene, 1,2-epoxypropane, 1,2-propanediol, propionic acid, and undefined species bound to protein (for propyl chloride). The addition of exogenous glutathione to the incubation mixture led to the production of S-(1'-propyl)glutathione and S-(2'-hydroxy-1'-propyl)glutathione. The ratio of the metabolites resulting from C1-C2 functionalization [propene, 1,2-propanediol, and S-(2'-hydroxy-1'-propyl)glutathione] to that resulting from C1 functionalization (propionic acid) increased as the halide progressed down the halide order chloride bromide, and iodide. Mechanisms which rationalize the distribution of propyl halide metabolites as a function of the halide are discussed. The preferred mechanism interprets that the results obtained are a consequence of the partitioning of the initial metabolic transformation between alpha-hydroxylation and halogen oxygenation pathways.

Animals↗
PubMed1981

Microsomal activation of thioacetamide-S-oxide to a metabolite(s) that covalently binds to calf thymus DNA and other polynucleotides.

In the presence of NADPH liver microsomes isolated from phenobarbital-pretreated rats catalyze the conversion of [3H]thioacetamide-S-oxide to a reactive intermediate(s) which covalently binds to calf thymus DNA, calf liver RNA, polyguanylic acid (poly(G)) and polyadenylic acid (poly(A)). The highest level of binding of radioactivity was obtained with poly(G), followed by poly(A), RNA and DNA. The incorporation of radioactivity into DNA was linear for 30 min and there was a requirement for NADPH for time-dependent covalent binding to occur. Performing the microsomal incubations in an atmosphere of 80% CO/20% O2 or adding partially purified anti cytochrome P-450 immune serum to the microsomal incubations inhibited the total metabolism of thioacetamide-S-oxide and had a small, but insignificant, inhibitory effect on binding of radioactivity to calf thymus DNA. Using a reconstituted monooxygenase system containing cytochrome P-450 purified from phenobarbital-treated rats we were unable to detect any metabolism of thioacetamide-S-oxide. Only background levels of radio-activity were incorporated into calf thymus DNA when microsomes isolated from phenobarbital-treated rats were incubated with [3H]thioacetamide in the presence of NADPH. These results suggest that thioacetamide-S-oxide is an obligatory intermediate in the metabolic activation of thioacetamide to a reactive metabolite(s) which binds to calf thumus DNA.

Acetamides↗
PubMed1981

Identification of the major protein adduct formed in rat liver after thioacetamide administration.

The in vivo covalent binding of the hepatocarcinogen thioacetamide to rat liver protein has been examined. Following administration of 3H- or 14C-labeled thioacetamide, the modified amino acids present in the hepatic cytosolic proteins were isolated by enzymatic digestion and ion-exchange chromatography. Approximately 70% of the radioactivity covalently bound to cytosolic protein was recovered in a compound which upon acid hydrolysis yielded lysine and radiolabeled acetate. Additional studies indicated the structure of this adduct was N-epsilon-acetyllysine.

Acetamides↗