Gillian M. Powell

Pulmonary toxicity of thioureas in the rat.

Administration of alpha-naphthylthiourea (ANTU) to rats causes damage to pulmonary endothelial cells and possibly mesothelial lining cells that together may account for the massive pleural effusion characteristic of thiourea toxicity. Using 35S-thiourea as a model compound, the extent of binding of 35S to lung proteins correlated well with the extent of edema, suggesting that the extent of binding of thiourea metabolites is a measure of lung toxicity. ANTU and phenylthiourea (PTU) compete for 35S binding to lung slices, suggesting that these toxins may act in a similar way. Binding of 35S in lung slices from resistant rats is much less than in controls, and resistance cannot be explained by differences in either whole body metabolism or redistribution of thiourea in vivo. Lung glutathione levels (in vitro and in vivo) in normal and resistant rats following thiourea administration were essentially the same. However, at doses of thiourea that cause pleural effusion, there was an increase in total lung glutathione. ImagesFIGURE 1. AFIGURE 1. BFIGURE 2. AFIGURE 2. B

The metabolic sulphation of polyethyleneglycols by isolated perfused rat and guinea-pig livers

1. It is shown that isolated perfused rat and guinea-pig livers can sulphate polyethyleneglycol 200 at rates of about 5 and 10 nmol/g per min, respectively. 2. In the guinea-pig about equal amounts of sulphated polyethyleneglycol 200 appear in the bile and in the perfusate, while in the rat about 99% appears in the latter. 3. Polyethyleneglycols 400 and 1000 are also sulphated in perfused guinea-pig liver but polyethyleneglycol 6000 is not. 4. Polyethyleneglycols are therefore not suitable solvents for xenobiotics which may undergo sulphation because of the likelihood of competition for sulphate.

The Fate of 2,6-Dimethoxy[U-14C]phenol in the Rat

Abstract1. The metabolic fate of 2,6-dimethoxy[U-14C]phenol, administered intravenously to rats at three dose levels (10–30 mg/kg body wt.), was investigated.2. The majority of injected radioactivity appeared in urine but significant amounts were eliminated via the bile (16.3–35.4%).3. The urinary radioactivity was associated with two metabolites identified as 2,6-dimethoxy[U-14C]phenylglucuronide and 2,6-dimethoxy[U-14C]phenylsulphate. The glucuronide conjugate predominated in the female rat while approximately equal amounts of the conjugates were produced by the male.4. The biliary metabolite was identified as 2,6-dimethoxy[U-14C]phenyl-glucuronide.

The toxicity of dimethoxyphenol and related compounds in the cat

Abstract The metabolic fate of 2,6-dimethoxyphenol, phenol and quinol (hydroquinone) were investigated in the cat. The nature of the urinary metabolic products was dependent upon the dose of the phenol administered, although in all cases the major detoxication products were sulfate conjugates. Hydroxylation of 2,6-dimethoxyphenol and phenol to the corresponding quinols is a major pathway and at relatively high doses unconjugated quinols were found in the urine. Experiments with para-substituted phenols suggest that quinol formation is an obligatory step leading to poisoning in the cat. 2,6-Dimethoxyquinol and quinol had no effect on mitochondrial respiration in vitro whereas the corresponding quinones were potent inhibitors. Inhibition was not observed in the presence of l -cysteine.

The Biodegradation of some Anionic Detergents in the Rat a Common Metabolic Pathway

1. The metabolism of the anionic detergents potassium decyl [35S]sulphate and potassium octadecyl [35S]sulphate was investigated in the rat. 2. The major route for elimination of radioactivity was urinary regardless of the route of administration. 3. Both surfactants were extensively degraded in vivo to yield a common metabolite, butyric acid 4-[35S]sulphate, the major urinary radioactive component. 4. Whole-body radioautography revealed the liver as the major site of cellular accumulation of radioactivity following administration of either compound indicating the liver as the major site of metabolism. 5. It is suggested that alkyl sulphates with even-numbered carbons are degraded by a common pathway involving omega-oxidation followed by beta-oxidation.

The enhanced biliary secretion of a taurine conjugate in the rat after intraduodenal administration of high doses of fenclozic acid

1. The metabolic fate of [14C]fenclozic acid (ICI 54450) in rat was determined after intraduodenal administration at different doses. 2. Increasing the dose from 2 to 100 mg/kg resulted in a five-fold increase in drug-related material secreted in bile. 3. At a dose of 2 mg/kg the taurine conjugate was a relatively minor metabolite, whereas at 100 mg/kg this conjugate was the major metabolite in bile and urine. 4. Enhanced biliary secretion of the taurine conjugate in rats receiving multiple doses of fenclozic acid results in exposure of the intestinal cells to much greater concn. of drug-related metabolites.

The fate of intravenously administered highly purified bovine testicular hyaluronidase (hyalosidase) in the rat

A highly purified commercial preparation of bovine testicular hyaluronidase (GL enzyme, Hyalosidase) was labelled with 125iodine without measurable loss of enzyme activity. The labelled preparation was administered intravenously into rats and the serum half-life of hyaluronidase was determined by measurement of both radioactivity and enzyme activity. The short half-life of the enzyme in plasma could not be accounted for by excretion in the urine and bile. Tissue distribution studies showed that the major site of uptake was the liver (59.7% of the recovered dpm). This rapid uptake by the liver could be reduced significantly by the pre-administration of yeast mannan or ovalbumin (a mannose-terminated glycoprotein). This suggests that the uptake of hyaluronidase by the liver is mediated by a mannose-specific receptor. Very little radioactivity was found in the heart (0.2% of the recovered dpm).

The Biodegradation of the Surfactant Undecyl Sulphate

1. The metabolism of the odd-numbered carbon chain surfactant, potassium undecyl [35S]sulphate in the rat was investigated. 2. The major route for elimination of radioactivity was the urine, regardless of the route of administration. 3. The surfactant was extensively degraded in vivo to yield propionic acid 3-[35S]sulphate, the major radioactive component in urine. A second urinary metabolite was identified tentatively as pentanoic acid 5-[35S]sulphate. 4. Whole-body autoradiography revealed the liver as the major site of metabolism. 5. The nature of the metabolic products of undecyl sulphate suggest that it is bio-degraded by initial omega-oxidation followed by beta-oxidation.

Conjugation of phenol by rat lung

Abstract The metabolism of [U- 14 C]phenol was studied in whole rat lung preparations and it was shown that [U- 14 C]phenol was extensively metabolized. The fate of [U- 14 C]phenol in isolated perfused rat lung preparations was the same when phenol was administered either intratracheally or systemically. [U- 14 C]Phenyl sulphate and [U- 14 C]phenyl glucuronide were the major metabolites thus demonstrating the presence of appropriate sulphotransferase and glucuronyl transferase activity in the whole lung. [U- 14 C]Phenol was not metabolized by rat pulmonary macrophages.

Renal Excretion of some Aryl Sulphate Esters in the Rat

The renal clearance of inulin, phenyl [35S]sulphate, naphthyl 2-[35S]-sulphate and 2-hydroxy-5-nitrophenyl [35S]sulphate was measured at various plasma concentrations in the rat.A considerable proportion of each ester was bound to plasma proteins in vivo and the ratio of 35S-labelled sulphate ester/inulin clearance demonstrated that all three esters are secreted by the renal cells.The contribution of the renal secretory process to the overall urinary excretion ranged between 22–59% (phenyl [35S]sulphate), 58–87% (naphthyl 2−[35S]sulphate) and 60–72% (2-hydroxy-5-nitrophenyl [35S]sulphate).These findings are discussed in relation to the detoxication of phenols by sulphate conjugation.