Sybil P. James

The acetylation of S-alkylcysteines by the rat.

Abstract Rats have been dosed with S-ethyl-, S-propyl-, S-butyl-, S-pentyl- and S-hexyl-cysteine, and the mercapturic acids excreted have been determined by paper and gas-liquid chromatography. N -(Ethyl thioacetyl)glycine is a metabolite of S-ethyl cysteine and has been determined by GLC; the higher cysteines did not form N -alkyl-thioacetylglycine metabolites. Rats dosed with S-butyl- and S-pentyl- cysteines excreted traces of the sulphoxide of the corresponding mercapturic acid. The amounts of mercapturic acid formed by rat liver slices from S-butyl, S-pentyl- and S-hexyl- l -cysteine have been determined. The synthesis and properties of N -(ethyl-, N -(propyl- and N -(butyl-thioacetyl)glycine, and of the sulphoxides of pentyl- and hexyl-mercapturic acid are described.

The absorption and metabolism of methyl cinnamate

Analysis of the gut contents of rats killed at intervals after dosage with methyl cinnamate or cinnamic acid suggested that both ester and acid were rapidly absorbed; at no time was more than 5% of the dose detected in the lower part of the gut. Not more than 9% of the administered methyl cinnamate was detected in the stomach as cinnamic acid whereas at least 40% of the small amounts of the dosed ester detected in the lower part of the gut was present as cinnamic acid. No ester was detected in the peripheral blood of dosed rabbits or rats and only traces were detected in portal and heart blood samples taken from dosed rats. Cinnamic acid and methanol were readily detected in the blood of rabbits and rats which had been dosed with methyl cinnamate. No qualitative or significant quantitative difference was detected in the metabolism of the ester as compared with the parent acid. In addition to the metabolites of cinnamic acid described in the literature p-hydroxyhippuric acid was excreted as a minor metabolite of both cinnamic acid and methyl cinnamate.

Mercapturic acid formation in the developing rat.

1. Young female rats dosed with 1-bromo[1-14C]propane excrete the same metabolites as adult females but in different relative proportions. Propylcysteine was detected as one of the metabolites in rats of all ages studied but represented a higher proportion of the total metabolites excreted in rats aged 5 and 11 days. 2. Hepatic GSH-S-alkytransferase activity was low in females at birth increasing up to the age of about thirty days. No activity was detected in the livers of the males at birth and up to 6 days of age; thereafter the level of activity increased up to 35-40 days. 3. Propylcysteine was excreted as prophylmercapturic acid and propylmercapturic acid sulphoxide by female rats of all ages. The amount of sulphoxide excreted relative to mercapturic acid excreted was higher in rats up to the age of 16 days than in older animals.

The metabolism of alicyclic ketones in the rabbit and rat.

Abstract1. Rabbits and rats dosed with cyclopentanone, cyclohexanone or cycloheptanone excrete traces of the corresponding 2-hydroxycycloalkylmercapturic acids.2. In each case small amounts of a second sulphur-containing metabolite are excreted. Mass spectroscopic evidence suggests that these metabolites are the sulphate esters of 2-hydroxycycloalkylmercapturic acids.3. Cyclopentyl and cycloheptyl glucuronides are the major metabolites of cyclopentanone and cycloheptanone in the rabbit.

Some Metabolites of S-Pentyl-L-cysteine in the Rabbit and Other Species

Abstract1. The metabolism of S-pentyl-L-cysteine has been investigated in the guinea pig, hamster, mouse, rabbit and rat and in vitro by liver slices of these animals and of the pigeon and by kidney slices of mouse, rabbit and rat.2. The amounts of pentylmercapturic acid, 3-(pentylthio)lactic acid and 3-(pentylthio)pyruvic acid excreted have been measured.3. All the species examined excreted pentylmercapturic acid, the amount varying from 2% of the dose by the guinea pig to 73% by the hamster. 3-(Pentylthio)pyruvic and 3-(pentylthio)lactic acids were not detected in the urine of the hamster or rat but were excreted by the other species in amounts approximately the same as those of pentylmercapturic acid.4. ‘Hydroxypentylmercapturic’ acids were excreted by mouse, rabbit and rat and were identified in the case of the rabbit and rat.5. 4-Carboxybutylmercapturic acid was identified in the urine of dosed mice, rabbits and rats. A further metabolite in rat urine was tentatively identified as 3-(4-carboxybutylth...

Some observations on the source of cysteine for mercapturic acid formation

Abstract Some types of mercapturic acid precursor have been shown to cause a fall in the total thiol content of rat liver homogenates and evidence is presented that this fall is due largely to a fall in the thiol groups of glutathione. The results given support the view that the initial reaction of mercapturic acid precursors is with glutathione rather than with tissue protein.

Glutathione Conjugation and Mercapturic Acid Formation in the Developing Rat, in vivo and in vitro

1. The levels of GSH-S-epoxidetransferase (GSH-S-transferase E, EC 2.5.1.18), gamma-glutamyl transpeptidase (EC 2.3.2.2) and S-substituted cysteine N-acetyltransferase have been measured in the liver and kidney of neonatal to adult rats. 2. GSH-S-epoxidetransferase and S-substituted cysteine N-acetyltransferase activities were less than 10% of the adult values in neonatal rats, rising gradually to reach adult values at about 40 days of age. Renal gamma-glutamyl transpeptidase activity was 27% of the adult value 2 days after birth and increased after 15 days reaching adult levels by 40 days. 3. The percentages of the doses of 1,2-epoxy-3-(p-nitrophenoxy)propane (ENPP) and of 1,2-epoxybutane, administered at the same dose level to rats aged 4 days to adult, excreted as the corresponding mercapturic acids in 24 h, were not significantly different. 4. Adult and 10 day old rats doses at the same dose level with ENPP excreted N-acetyl-S-[2-hydroxy-3-(p-nitrophenoxy)propyl]-L-cysteine (ENPP-MA) at the same rate. 5. In addition to ENPP-MA, dosed rats under 13 days of age excreted the corresponding substituted cysteine. 6. The correlation between results in vitro and in vivo is discussed.

Metabolism of 1,3-dibromopropane

Oral administration of 1,3-dibromopropane (2 mmol/kg) to rats resulted in a marked decrease in the level of hepatic glutathione (GSH). Sulphur-containing [14C]-metabolites were excreted in the bile of rats dose with 1,3-bromo[14C]propane and were subjected to enterohepatic cycling. After an oral dose of 1,3-dibromo[14C]propane, peak levels of radioactivity were rapidly attained in the blood and were maintained for several hours; approximately equal amounts of radioactive material were excreted in urine and expired air. Several radioactive metabolites were excreted in urine; a major metabolite was N-acetyl-S-[1-bromo-3-propyl]-cysteine.

Toxicity of benzyl cyanide in the rat.

Lethal doses of benzyl cyanide in the rat were 0.64 mmol/kg (i.p.), 1.8 and 2.6 mmol/kg (p.o.) for female and male rats, respectively. Sublethal oral doses of benzyl cyanide were nephrotoxic causing increased excretion of protein, amino acids and glucose. Cyanide was slowly liberated from the dosed nitrile and excreted as cyanide and thiocyanate, the proportion of the former increasing with increasing i.p. dose and with the highest oral dose. The oral cyanide antidote was ineffective against benzyl cyanide and the intravenous antidote, Kelocyanor (cobalt edetate), had little beneficial effect.

Metabolites of 1,2-epoxy-3-phenoxy- and 1,2-epoxy-3-(p-nitrophenoxy)propane.

1. Rabbits and rats dosed with 1,2-epoxy-3-phenoxypropane excrete 2-hydroxy-3-phenoxypropionic acid and N-acetyl-S-(2-hydroxy-3-phenoxypropyl)-L-cysteine. 2. Rabbits and rats dosed with 1,2-epoxy-3-(p-nitrophenoxy)propane excrete 2-hydroxy-3-(p-nitrophenoxy)propionic acid, N-acetyl-S-[2-hydroxy-3-(p-nitrophenoxy/propyl)propyl]-L-cysteine and p-nitrophenol. 3. The administration of either epoxide to the rat produces a marked fall in hepatic GSH level. 4. The biliary excretion of metabolites of 1,2-epoxy-3-(p-nitrophenoxy)-propane is described.