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Biomedical subjects

C G Curtis

Publications and source records attributed to C G Curtis.

At least 19 recordsLinked to original sources
PubMed1991

The role of the liver in the production of free radicals during halothane anaesthesia in the rat. Quantification of N-tert-butyl-alpha-(4- nitrophenyl)nitrone (PBN)-trapped adducts in bile from halothane as compared with carbon tetrachloride.

Halothane or CCl4 was co-administered with the spin trap N-tert-butyl-alpha-(4-nitrophenyl)nitrone (PBN) to rats fitted with bile duct cannuli or to isolated perfused liver preparations. Rats maintained under halothane anaesthesia generated significant amounts of free radicals, and 5-9 nmol was excreted in bile over 1 h. No adducts were detected in urine or plasma. The hepatic origin of these free radicals was confirmed by studies on isolated perfused livers where the addition of halothane to the perfusate resulted in the biliary elimination of the same PBN-trapped radical adducts. Similarly, following CCl4 administration, the same radical species were eliminated in bile in the whole animal and the perfused liver preparation. In the perfused liver, over 3 h the total biliary elimination of radicals derived from halothane or CCl4 (administered at equimolar concentrations) was approximately the same (5-7 nmol); however, the elimination of halothane-derived radicals was more rapid over the first 1 h.

Animals↗
PubMed1991

The uptake of oestrone from the lumen of the isolated perfused rat gut.

1. In the isolated perfused rat gut oestrone was not taken up from the perfusate but was rapidly taken up from the gut lumen when administered in dimethyl sulphoxide or in 10% acetone in water. 2. Uptake from corn oil was much slower and the rate was concentration-dependent. 3. When given in dimethyl sulphoxide or in aqueous acetone, the residual oestrone in the gut lumen was largely unchanged, with only about 10% being present as the glucuronide. Of the oestrone in the gut perfusate, some 40% was glucuronidated. 4. No evidence was obtained for any reduction or hydroxylation, or for any sulphation, during uptake of oestrone by the gut. 5. No secretion of oestrone or its metabolites into lymph could be detected.

Animals↗
PubMed1991

Sulphation of the flavonoids quercetin and catechin by rat liver.

1. The isolated perfused rat liver forms three sulphated metabolites from each of the flavonoids, quercetin and catechin: these are secreted into the bile and the perfusate. 2. Quercetin gives two double conjugates, containing sulphate and glucuronic acid, and one sulphate: catechin gives one such double conjugate and two sulphates. 3. This sulphation is not inhibited by 60 microM 2,6-dichloro-4-nitrophenol which almost completely inhibits the sulphation of harmol in this perfused liver system. 4. The sulphation of harmol by the perfused liver is not inhibited by the flavonoids. 5. Unfractionated sulphotransferases from rat liver catalyse sulphate conjugation of quercetin and catechin in vitro by a reaction inhibited by pentachlorophenol or dichloronitrophenol: the flavonoids inhibit the sulphation of 4-nitrophenol by this system. 6. The results with the two systems are discussed and shown to be compatible.

Animals↗
PubMed1990

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.

Animals↗
PubMed1990

The effects of drugs, other foreign compounds, and cigarette smoke on the synthesis of protein by lung slices.

The incorporation of 14C-leucine into rabbit lung slices was monitored in the absence and presence of selected drugs and chemicals relevant to the perturbation of lung function and the development of lung disease. Known inhibitors of protein synthesis (cycloheximide and ricin) inhibited the incorporation of 14C-leucine. Marked inhibition was also recorded with the lung toxins paraquat and 4-ipomeanol. By contrast, orciprenaline, salbutamol, and terbutaline were without effect although some response was recorded with isoprenaline. The filtered gas phase of cigarette smoke and acrolein, one of its components, were inhibitory but protection was afforded by N-acetylcysteine. It is suggested that the inhibitory effects of cigarette smoke may be due to its acrolein content. It is further suggested that the use of lung slices and measurements of 14C-leucine incorporation provide valuable means for monitoring potential pulmonary toxins.

Animals↗
PubMed1989

Glutathione-dependent dechlorination of 1,6-dichloro-1,6-dideoxyfructose.

The metabolism of 14C- and 36Cl-labelled 1,6-dichloro-1,6-dideoxyfructose (DCF) was studied in the isolated perfused rat liver system. Dechlorination of DCF occurred in the liver and erythrocytes and was GSH-dependent. The GSH conjugate formed was identified by 13C and 1H n.m.r. as the 6-chlorofructos-1-yl-SG conjugate. It is proposed that the GS- anion attacks the low steady-state concentration of the reactive keto form of DCF and that the conjugate formed cyclizes to the dominant beta-anomer. 6-Chlorofructos-1-yl-SG conjugate of hepatic origin is excreted into bile, whereas that produced in erythrocytes does not enter the liver.

Animals↗
PubMed1989

Isolated perfused liver technology for studying metabolic and toxicological problems.

The isolated perfused liver system is a versatile model for investigating the effects and mechanisms of action of hepatotoxins and the metabolism of endogenous and exogenous compounds. The interpretation of metabolic data and apparent toxic events is dependent upon the viability and reproducibility of the model. In this study, a new approach has been undertaken to assess the viability of isolated liver preparations. This has involved the continuous monitoring of multistage processes namely, the synthesis and secretion of radiolabelled proteins, glycoproteins and lipoproteins on the one hand and the uptake of macromolecules by receptor-mediated endocytosis on the other. The consistency of these complex integrated processes from one liver to another and in particular the steady-state rate of production of radiolabelled macromolecules over 6h perfusion periods suggests that this model can be used with confidence for metabolic/toxicological investigations. The selectivity of the responses to chemical challenge(s) shows that this system can be exploited for (a) screening potential hepatotoxins; (b) identifying areas of metabolism which are affected and (c) advancing basic knowledge of liver biochemistry.

Animals↗
PubMed1988

Evidence for filaggrin as a component of the cell envelope of the newborn rat.

A substrate of transglutaminase, specific to the epidermis, was identified, by fluorescent and radioactive labelling with the lysine analogues dansylcadaverine and [14C]putrescine respectively, in newborn-rat epidermal homogenates and whole-skin organ cultures. The labelled analogues were preferentially incorporated into the stratum-corneum protein filaggrin in a Ca2+-dependent manner in both 'in vitro' systems. When filaggrin was labelled in vivo with [3H]histidine and then incubated with rat epidermal preparations, the label was rendered SDS/thiol-insoluble. Incorporation of [3H]filaggrin into the insoluble envelope fraction was Ca2+-dependent and inhibited by EDTA and exogenous amines. Antisera to newborn-rat filaggrin cross-reacted with purified newborn-rat cell envelopes, and this reaction was blocked by adsorbing the antiserum with purified filaggrin. Quantification of the 'envelope-bound' filaggrin showed it to be a significant component, accounting for approx. 10% of the cell-envelope protein.

Animals↗
PubMed1988

Localization of transglutaminase activity in type II epithelial cell cultures and elevation of enzyme activity in lungs of rats instilled with quartz.

Transglutaminase activity, assessed by the incorporation of [14C]-putrescine into N-acetylated dephosphorylated beta-casein, was not detectable in sonicates of alveolar macrophages and fibroblasts but was located in all preparations of rat alveolar type II cells. Enzyme activity was induced in these cells up to 7 days in vitro but not stimulated further by the direct addition of quartz to the cultures. Transglutaminase activity in whole lung sonicates increased significantly after short-term exposure to DQ-12 quartz. An increase in the numbers of type II cells and subsequent release of activated transglutaminase, concomitant with a quartz-induced elevation in lung calcium levels and potential protein substrates, is likely to lead to an increase in protein crosslinking both in the alveolar space and interstitium.

Animals↗
PubMed1988

Tissue distribution and excretion of amodiaquine in the rat.

14C-Labelled amodiaquine ([14C]AQ) has been administered to male Wistar rats by oral and intravenous routes (n = 6 for each route of administration). Excretion of total 14C-activity was predominantly in the faeces after both oral and intravenous administration. After oral administration 86 +/- 8.3% (mean +/- s.d.) of the 14C administered had been excreted (77 +/- 9% in the faeces, 7 +/- 1% in the urine and 2 +/- 2% in cage washings) over 72 h. Of the 14C administered, 4 +/- 1% was recovered from the tissues, and this was widely distributed, with the main organs of accumulation being kidney, liver, red bone marrow and spleen. After intravenous administration, 102.6 +/- 9.7% of the 14C had been excreted (90.9 +/- 9.6% in faeces, 10.9 +/- 0.8% in urine and 0.5 +/- 0.2% in cage washings) over 72 h. High-performance liquid chromatographic analysis of urine and faeces samples following oral administration of 14C-AQ (8.6 mg kg-1; base) revealed recoveries of 210 +/- 70 micrograms amodiaquine (AQ) and 123 +/- 32 micrograms desethylamodiaquine (AQm) in the faeces, and 2.4 +/- 0.5 micrograms AQ and 18.5 +/- 4.1 micrograms AQm in the urine. Female Wistar rats (n = 6) each received [14C]AQ orally and were killed at the following times: 0.5, 1, 3, 6, 24 and 48 h. Autoradiographs were prepared from each animal and these revealed significant amounts of radioactivity in the tissues at 48 h. This was accumulated maximally by liver and kidney. Radioactivity was detected in bone marrow at 48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Sulphoconjugation and sulphohydrolysis.

The formation of sulphoconjugates is a ubiquitous phenomenon and the addition of the sulphate moiety to a variety of endogenous and exogenous molecules dramatically alters their physico-chemical properties and also their biological functions. Large numbers of different types of sulphoconjugate exist and their formation is catalysed by the versatile sulphotransferases. An equally versatile family of enzymes, the sulphohydrolases exist that are capable of accomplishing the reverse reaction. This paper comprises an appraisal of sulphoconjugation and sulphohydrolysis in the metabolism of xenobiotics and addresses the wider issues of sulphur availability and the interplay between mammalian and microbial enzyme systems in the sulphate cycle.

Animals↗
PubMed1988

The inhibition by chlorate of the sulphation of polyethyleneglycol in the isolated perfused guinea pig liver.

1. The sulphation of polyethyleneglycol 200 by the isolated perfused guinea pig liver is inhibited to about 60% by 10 mM ClO3- in the plasma of the perfusate when the concentration of SO4(2-) therein is 1.18 mM. 2. The inhibition is almost complete when the concentration of SO4(2-) is about 0.1 mM, a level which can be achieved by using a modified Ringer-bicarbonate solution, devoid of sulphate, to prepare the perfusate. 3. Chlorate, presumably through its action on ATP-sulphurylase, may therefore be a useful inhibitor of sulphation in the isolated perfused liver when the activity of the sulphurylase is rate-limiting. 4. The rate of bile production in the presence of chlorate is no different from that in its absence showing that, in the time scale of the perfusion, chlorate is not a general liver poison. 5. When the synthesis of PAPS is not rate-limiting, as in the sulphation of oestrone metabolites by rat liver, chlorate has no effect on the rate of sulphation.

Animals↗
PubMed1987

Metabolism in the rat of potassium nonan-5-sulphate, a symmetrical anionic surfactant.

1. The metabolism of potassium nonan-5-[35S]sulphate, a symmetrical secondary alkylsulphate ester, was investigated in the rat. Oral administration of the radiolabelled ester was followed by the elimination of the majority of radioactivity in the urine. 2. Potassium nonan-5-[35S]sulphate is degraded in vivo to produce at least three radiolabelled sulphate esters. 3. The same metabolites were produced by isolated rat livers perfused with potassium nonan-5-[35S]sulphate. 4. The three radioactive metabolites were identified by combined g.l.c.-mass spectroscopy as the unchanged parent ester, nonan-1-ol-5-sulphate and nonanoate-5-sulphate. 5. The nature of the latter two metabolites indicates that potassium nonan-5-sulphate is metabolized by omega-oxidation only and, moreover, the alkylsulphate ester is metabolized only at one end of the molecule.

Anesthesia↗
PubMed1987

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.

Animals↗
PubMed1987

The metabolism of oestrone and some other steroids in isolated perfused rat and guinea pig livers.

1. Oestrone is rapidly taken up by isolated perfused rat liver (t 1/2 less than 2 min) to yield at least 10 metabolites excreted in the bile; peak concentration occurs after about 20 min. 2. Sulphated metabolites of oestrone appear in the perfusate, reaching peak concentration at about 10 min, and then slowly disappear. 3. Sulphated metabolites of oestrone accumulate in the liver during the first 10 min. They are partly converted to sulphoglucuronides (steroid 3-sulphates conjugated with glucuronic acid in the D ring) and partly hydrolysed to be reconjugated as glucuronides. 4. The major biliary metabolites of oestrone in isolated perfused rat liver are glucuronides and sulphoglucuronides, but free steroids, sulphates and polar metabolites are also so excreted. 5. The isolated perfused guinea pig liver also rapidly takes up oestrone (t 1/2 less than 2 min) but, in contrast to the rat, a single glucuronide is the only quantitatively important metabolite in the bile: it is also extensively secreted into the perfusate where it reaches peak concentration at about 10 min. 6. In perfused guinea pig liver, oestrone does not form sulphoglucuronides, and sulphates are only minor metabolites; this is not due to lack of the appropriate sulphotransferase because oestradiol 17 beta-(beta-D-glucuronide) is extensively sulphated in this system. 7. Oestradiol 17 beta-(beta-D-glucuronide) is not cholestatic in the isolated perfused guinea pig liver although it is in rat liver. 8. There is a similar species difference in the metabolism of dehydroepiandrosterone in the two species: the rat forms sulphoglucuronides, the guinea pig does not. 9. The perfused rat liver extensively hydroxylates, presumably on the D ring, 17-deoxyoestrone and 17-deoxydehydroepiandrosterone. 10. The inability of perfused guinea pig liver to form sulphoglucuronides from oestrone or dehydroepiandrosterone is probably due to its restricted ability to hydroxylate the D ring of steroids. 11. Both rat and guinea pig biles contain beta-glucuronidase, about 80 and 230 sigma units/ml, respectively.

Animals↗
PubMed1985

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).

Animals↗
PubMed1978

Biliary excretion of cyclohexylphenyl 4-[35S]sulphate in the guinea pig.

The metabolic fate and mode of excretion of cyclohexylphenyl 4-[35S]sulphate were studied in the guinea pig. Up to 54.8% of the dose appeared in the bile, the majority as unchanged ester. Substantial amounts of hydroxylated cyclohexylphenyl 4-[35S]sulphate were also excreted in the bile together with minor amounts of the corresponding glucuronic acid conjugate. When isolated guinea-pig livers were perfused with cyclohexylphenyl 4-[35S]sulphate the biliary components were the same as those in the intact animal, although the relative concentration of the hydroxylated derivative was significantly greater. When the hydroxylated derivative was re-injected into guinea pigs it was excreted almost entirely unchanged in the bile. However, in the rat, it was excreted in the bile as a glucuronic acid conjugate. These findings are discussed in relation to studies carried out in the rat [Hearse, Powell, Olavesen & Dodgson (1969) Biochem. Pharmacol. 18, 181--195] and to differences in enzyme activities in rat and guinea-pig liver. The results are also discussed in terms of the molecular-weight threshold for the excretion of anions in guinea-pig bile.

Animals↗