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R A Neal

Publications and source records attributed to R A Neal.

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Studies of the metabolism of parathion with an apparently homogeneous preparation of rabbit liver cytochrome P-450.

The metabolism of parathion has been examined by use of a reconstituted mixed-function oxidase enzyme system isolated from the livers of phenobarbital-pretreated rabbits. The cytochrome P-450 used in these studies was apparently homogeneous as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and by assay of the preparation for contaminating microsomal enzymes and enzyme activity. These studies revealed that the apparently homogeneous preparation of cytochrome P-450, in the presence of the appropriate cofactors, can catalyze the conversions of parathion to both paraoxon and diethyl phosphorothioic acid. The present studies have also shown that parathion is metabolized by the reconstituted mixed-function oxidase enzyme system to diethyl phosphoric acid, a product which, in previous studies with intact liver microsomes, had been thought to arise exclusively from the hydrolysis of paraoxon by a microsomal esterase(s). The available data suggest that all three of the products of the metabolism of parathion by the reconstituted mixed-function oxidase enzyme system, namely, paraoxon, diethyl phosphorothioic acid, and diethyl phosphoric acid, are formed nonenzymatically by breakdown by different pathways of a common enzymatically formed intermediate. This common intermediate is thought to be the sulfine derivative of parathion formed in the mixed-function oxidase-catalyzed addition of an oxygen atom to one of the unshared electron pairs of the thiono-sulfur atom.

Animals↗
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Distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J, DBA/2J, and B6D2F1/J mice.

The strains of mice, C57BL/6J, DBA/2J, and B6D2F1/J, have been used as models to study the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The distribution, excretion, and metabolism of this compound was studied in male C57BL/6J, DBA/2J, and B6D2F1/J mice following the intraperitoneal administration of radiolabeled TCDD at a dose of 10 micrograms/kg. In all strains, the liver and adipose tissue were the major sites for the accumulation of 3H-TCDD, with more 3H-TCDD being distributed to the livers of the C57BL/6J and B6D2F1/J strains as compared to the DBA/2J strain. While in all strains the feces were the major route of elimination, the total amount of 3H-TCDD-derived radioactivity excreted in the feces amounted to approximately 72% of the original dose in the C57BL/6J and B6D2F1/J strains whereas this was only 54% in the DBA/2J strain. The half-lives for the cumulative excretion of radioactivity in the feces were similar in all strains. The half-life for the excretion of radioactivity in the urine was considerably greater in the DBA/2J strain as compared to the C57BL/6J and B6D2F1/J strains. The estimated half-lives for the total cumulative excretion of 3H-TCDD-derived radioactivity by all routes was 11.0, 24.4, and 12.6 days for the C57BL/6J, DBA/2J, and B6D2F1/J strains, respectively. Greater than 85% of the total radioactivity excreted in urine, bile, and feces from all three mouse strains was present as metabolites of TCDD.

Animals↗
PubMedDate not supplied

Studies on the mechanism of toxicity and of development of tolerance to the pulmonary toxin, alpha-naphthylthiourea (ANTU).

The in vivo administration of the radiolabeled lung toxin alpha-naphthylthiourea (ANTU) to rats leads to the covalent binding of radioactivity to the macromolecules of the lung and liver. In contrast, very little radioactivity is bound in these organs when an equal amount of the 14C-labeled oxygen analog of ANTU, 14C-alpha-naphthylurea (ANU), is administered. In addition, ANU is essentially nontoxic to rats. ANTU is metabolized in vitro by lung and liver microsomes to an intermediate which covalently binds to the macromolecules of the microsomes. This covalent binding, which requires NADPH, leads to a decrease in mixed-function oxidase activity and to a decrease in the level of cytochrome P-450 detectable as its carbon monoxide complex. Incubation of microsomes with ANTU in the absence of NADPH or with ANU in the presence of NADPH, has no effect on these parameters. Pretreatment of rats with small nonlethal doses of ANTU daily for 5 days brings about a decrease in the activity of the mixed-function oxidase enzyme system in the lung which metabolizes parathion. In addition, this pretreatment decreases the toxicity of ANTU and leads to a decrease in the amount of radioactivity bound to the macromolecules of the lung when the animals are given a lethal dose of 35S-ANTU. These data suggest that the lung toxicity of ANTU is brought about by its metabolic activation and covalent binding to lung macromolecules.

Animals↗