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Biomedical subjects

L L Smith

Publications and source records attributed to L L Smith.

At least 361 records · Page 20Linked to original sources
PubMedDate not supplied

The pathology and biochemistry of paraquat.

After the administration of paraquat to rats the lung is the organ most severely damaged. The pathology in the lung can be divided into two distinct phases: (1) a destruction phase lasting a few days with damage to the type I and type II alveolar epithelial cells, oedema and haemorrhage (most of the rats which die after dosing with paraquat do so during this phase); (2) a reparative phase with regeneration of the epithelium and, in areas of severe damage, a characteristic proliferation of fibroblasts. In both phases of the lesion the death of the rats results from anoxia. Paraquat is selectively accumulated by the rat lung in comparison with other tissues and this accounts, at least in part, for the specific toxic effect in this organ. The accumulation into the lung was shown by in vitro studies to depend on energy and is inhibited by various endogenous and exogenous compounds. This uptake process is not that which has been described for 5-hydroxytryptamine and evidence is presented to suggest that the type I and type II alveolar epithelial cells are sites of accumulation. When paraquat is present in lung cells, it undergoes a cyclical reduction and oxidation with the production of superoxide anion. This radical may lead directly or indirectly to the formation of lipid peroxides and hence to cell death. However, paraquat stimulates the pentose-phosphate pathway and both reduces the level of NADPH and inhibits fatty acid synthesis in the lung. These effects occur when there is only minimal ultrastructural damage to the lung cells. It is suggested, therefore, that the primary mechanism of toxicity of paraquat is the extreme oxidation of NADPH which inhibits vital physiological processes and renders the cell more susceptible to attack from lipid hydroperoxides.

Animals↗
PubMedDate not supplied

High performance liquid chromatography of tamoxifen and metabolites in plasma and tissues.

An isocratic reversed-phase high performance liquid chromatographic method for the determination of tamoxifen and its metabolites in plasma and tissues is described. Plasma or tissue homogenate was extracted with methanol/dimethyl sulphoxide (4:1 v/v). The supernatant after centrifugation was separated on a BDS-Hypersil column with methanol/0.5 M ammonium acetate (75:25 v/v) as the mobile phase. The recoveries of tamoxifen added to plasma and liver tissue homogenate by the extraction procedure were 102 +/- 1.6 and 98 +/- 2.4% (mean +/- SD, n = 6), respectively. The solutes were detected at 280 nm with a detection limit of 0.25 micrograms/mL for tamoxifen.

Animals↗
PubMedDate not supplied

Species differences in the metabolic activation of tamoxifen into genotoxic derivatives: risk assessment in women.

Rats and Rhesus monkeys are compared in their response to tamoxifen treatment, with particular reference to tamoxifen-related liver DNA damage and bioactivation of tamoxifen by isolated microsomes in vitro. Monkeys, treated with tamoxifen, accumulate in their livers a metabolite of tamoxifen, N,N-didesmethyl tamoxifen, with powerful inhibitory activity on cytochrome P450-dependent drug metabolism. The accumulation of this metabolite in the monkeys may limit the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and, in this way, protect against the formation of DNA adducts. This metabolite is also found in the liver and serum of patients taking tamoxifen, but more work is needed to determine whether inhibition of tamoxifen bioactivation also exists in the human patient in vivo and, if so, to what extent and in which organ.

Animals↗
PubMedDate not supplied

Cholesterol autoxidation 1981-1986.

Literature published between 1980 and 1986 dealing broadly with the topic of cholesterol autoxidation is reviewed. The review builds on the detailed 1981 monographic treatment of the topic by the author and covers new items of chemistry, analysis, and metabolism.

Animals↗
PubMedDate not supplied

Recognition of D-homoannulation by proton and carbon NMR spectra.

One-and two dimensional proton and carbon NMR spectra of the D-homoannulated rearrangement product of triamcinolone (9 alpha-fluoro-11 beta,16 alpha,17 alpha, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione) establish its structure as that of 9 alpha-fluoro-11 beta,16 alpha,17 alpha-trihydroxy-17 beta-hydroxy-methyl-D-homoandrosta-1,4-diene-3,17 alpha-dione. These methods accord ready recognition of D-homoannulation of C21-17-hydroxy-20-ketosteroids.

Androstenols↗
PubMedDate not supplied

Characterization of the interaction of 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6,-tetramethyl- cyclohexane-1,3,5-trione with rat hepatic 4-hydroxyphenylpyruvate dioxygenase.

The synthetic beta-triketones are a novel family of chemicals, developed as herbicides that have activity on grass and broadleaf weeds and are selective in corn. Toxicological evaluation of a number of these chemicals has established that they interfere with rat hepatic tyrosine catabolism in vivo by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). This paper describes the kinetics of inhibition of rat hepatic HPPD in vitro by the representative beta-triketone 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6- tetramethylcyclohexane-1,3,5-trione (1). A marked inhibition of rat hepatic HPPD was observed when 1 was incubated with the enzyme for 3 min at 37 degrees C prior to the initiation of the enzyme reaction by the addition of substrate. In this system, a concentration of 200 nM 1 resulted in a > 90% loss of HPPD activity, and an apparent IC50 was established at approximately 50 nM. The rate constant for the inactivation of HPPD by 1 was (1.5 +/- 0.2) x 10(-5) s-1 nM-1 as determined by progress curve data of oxygen consumed by HPPD with time. This inhibition is reversible in that the enzyme-inhibitor complex slowly dissociates, with approximately 5.5 +/- 0.6% of the enzyme activity being recovered by 6 h at 25 degrees C (t1/2, 25 degrees C, estimated at 101 +/- 14 h). In short, our studies establish 1 to be a tight-binding inhibitor of rat hepatic HPPD in vitro. This inhibition is characterized by the rapid inactivation of HPPD by the formation of an enzyme-inhibitor complex that dissociates extremely slowly with recovery of enzyme activity.

4-Hydroxyphenylpyruvate Dioxygenase↗