Watson D. Reid

Chloroform toxicity in mice: Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules

Abstract Chloroform (CHCl 3 ) treatment caused centrolobular hepatic necrosis in mice of both sexes whereas renal necrosis was observed only in male mice. Following administration of 14 CHCl 3 to mice, substantial amounts (about 3 mmole/g) of radiolabeled material were covalently bound to proteins in the liver and kidney. The amount of convalent binding paralleled the extent of renal and hepatic necrosis both in normal animals and in male mice pretreated with either phenobarbital or piperonyl butoxide, agents which induce or block, respectively, microsomal drug metabolizing enzymes. These results suggest that the covalent binding is due to a metabolite of CHCl 3 . Evidence that the covalent binding is causally related to the tissue necrosis was obtained from autoradiograms showing that the radioactivity is located mainly in the necrotic lesions.

Studies on the mechanism of the lung toxicity of paraquat: Comparison of tissue distribution and some biochemical parameters in rats and rabbits

Abstract After iv injection of [14C]paraquat (20 mg/kg) tissue localization was preferential in lungs of rats as well as rabbits although the latter did not show any histopathologic or biochemical signs of lung damage. No preferential subcellular localization of [14C]paraquat was found in lungs of either species, but all subcellular levels decreased more rapidly in the rabbit than in the rat. [14C]Paraquat was not covalently bound to tissue macromolecules. In vitro measurements of lipid peroxidation, H2O2 formation and lung lysosomal stability failed to account adequately for the lung damage in the rat.

Bromobenzene Metabolism and Hepatic Necrosis

Treatment of rats with Phenobarbital stimulates the metabolism of bromobenzene and potentiates the hepatic necrosis elicited by the hydrocarbon. In contrast, administration of SKF 525-A or of piperony

3-methylcholanthrene blocks hepatic necrosis induced by administration of bromobenzene or carbon tetrachloride

Abstract Prior administration of 3-methylcholanthrene (3-MC) to rats blocked the centrolobular hepatic necrosis induced by bromobenzene, chlorobenzene, or α-chloronaphthalene and partially blocked the hepatotoxic effect of carbon tetrachloride. 3-MC treatment enhanced the overall rate of 14C-bromobenzene metabolism but inhibited the covalent binding of 14C-labeled material to liver macromolecules in rats. In contrast, 3-MC administration to mice prevented neither the covalent binding nor the hepatotoxic effects of 14C-bromobenzene. These results support the hypothesis that chemically unreactive substances, such as bromobenzene, cause tissue lesions through the formation of covalent bonds between a chemically reactive metabolite and tissue macromolecules.

Mechanism of renal necrosis induced by bromobenzene

Abstract Treatment of mice or rats with a single intraperitoneal dose of [ 14 C]-bromobenzene or [ 14 C]-chlorobenzene produced necrosis of the proximal convoluted renal tubules within 24–48 hr. The development of renal necrosis was associated with the covalent binding of substantial amounts of radiolabeled material to kidney proteins, and autoradiograms revealed that most of the covalently bound material was localized within the necrotic tubular cells. Prior inhibition of [ 14 C]-bromobenzene metabolism in vivo with piperonyl butoxide blocked both the necrosis and the binding, suggesting that the necrosis and binding are caused by a toxic metabolite. Studies on the metabolism and covalent binding of [ 14 C]-bromobenzene in hepatic and renal microsomes in vitro were compatible with the interpretation that the renal necrosis was caused by a metabolite formed in the liver and transported by the circulation to binding sites in the renal tubules.

Biochemical Mechanism of Hepatic Necrosis Induced by Aromatic Hydrocarbons

Rats or mice developed centrolobular hepatic necrosis within 24 h after an intraperitoneal injection of 14C-bromobenzene or other radiolabeled halogenated aromatic hydrocarbons. The hepatic

Enzymic radioassay for acetylcholine and choline in brain

Abstract This assay for acetylcholine (ACh) or choline in extracts of rat brain involves the isolation of the choline ester by high-voltage paper electrophoresis, alkaline hydrolysis of ACh to choline, and the quantitative enzymic conversion of choline to a radioactive derivative, P 32 -phosphorylcholine. The method is specific, is applicable to large numbers of tissue samples, and has a blank value of about 3 nanograms of choline.

The interaction of norepinephrine and prostaglandin E1 on the adenyl cyclase system of human and rabbit blood platelets

Prostaglandin E1 markedly increased the formation of cyclic [3H]AMP from labeled adenine in human and rabbit blood platelets. Norepinephrine alone had no stimulatory effect, but it reduced cyclic AMP levels elevated by prostaglandin E1. Phentolamine overcame the inhibitory effect of norepinephrine, whereas propranolol did not. Homogenization of platelets reduced, but did not abolish, the inhibitory effect of norepinephrine on adenyl cyclase activity induced by prostaglandin E1.

Metabolism of foreign compounds by alveolar macrophages of rabbits

Abstract Alveolar macrophcges of rabbits acetylated p-aminobenzoic acid to the same extent as did lung parenchyma and liver. However, microsomes isolated from macrophages lacked detectable activity of aryl hydrocarbon hydroxylase, even in animals treated with 3-methylcholanthrene, an inducer of this enzyme in liver and lung. Similarly, bromobenzene was metabolized by microsomes prepared from liver and lung but not from alveolar macrophages.

Serotonin in Brain: Functional Considerations

Publisher Summary The discovery that reserpine impairs the storage of 5-HT and catecholamines has focused attention on the possible role of these biogenic amines in brain function and in mediating the pharmacologic and behavioral effects of the drug. This chapter reviews the functional significance of brain 5-HT. NE and 5-HT modulate opposing systems in the brain. The excitatory effects of 5-HTP have been used as a major argument against the view that 5-HT is the trophotrophic hormone. However, there is new evidence that these excitatory effects are caused through the release of NE. If only one of the amines is altered, the effects on physiologic behavior and EEG might suggest which neuronal pathway it modulates. The function of brain NE may be inferred from the effects of free catecholamines released from normal sites of storage and protected from monoamine oxidase (MAO). Reserpine in doses that reduce the brain levels of catecholamines and 6-HT by 55% produces obvious sedation and doses that decrease the levels by 70 to 80% evoke marked sedation and a syndrome of signs typical of trophotrophic stimulation including blepharospasm, extreme miosis, enhanced light reflex, diarrhea, and increased muscle tone.