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Biomedical subjects

D G Upshall

Publications and source records attributed to D G Upshall.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1987

The fate of 2-chlorobenzylidene malononitrile (CS) in rats.

1. The fate of 3H-ring labelled, 14C-cyanide labelled and (14C = C) side chain labelled 2-chlorobenzylidene malononitrile (CS), 2-chlorobenzyl alcohol and 2-chlorobenzyl malononitrile (dihydro CS) in rats and isolated rat liver cells has been examined. 2. CS was administered both i.v. and i.g. to rats at doses from 0.08 to 159 mumol/kg and in most cases the greatest proportion of the dose was eliminated in the urine (44-100%). The principal urinary metabolites were 2-chlorohippuric acid, 1-O-(2-chlorobenzyl) glucuronic acid, 2-chlorobenzyl cysteine and 2-chlorobenzoic acid. Lesser amounts of 2-chlorophenyl acetyl glycine, 2-chlorobenzyl alcohol and 2-chlorophenyl 2-cyano propionate were identified. 3. The major urinary metabolite from 2-chlorobenzyl alcohol was 2-chlorohippuric acid (43%), 2-chlorobenzyl cysteine, 2-chlorobenzoic acid and 2-chlorobenzyl glucuronic acid were identified. 4. The products of dihydro-CS metabolism were 2-chlorophenyl acetyl glycine, 2-chlorophenyl 2-cyanopropionate and 2-chlorophenyl proprionamide. 5. Urinary thiocyanate levels increased with the dose of CS up to 159 mumol/kg. At 212 mumol/kg there was a large increase in the amount of thiocyanate produced (molar conversion: 21.5-29.9%). Similarly malononitrile, the hydrolysis product of CS, gave a dose related increase in urinary thiocyanate levels. However at a higher dose (212 mumol/kg) the molar conversion was greater than 60%. 6. The metabolism of CS by isolated rat liver cells confirmed the results in vivo but demonstrated a marked limitation of this preparation to form conjugates. 7. It is concluded that CS in vivo is hydrolysed mainly to 2-chlorobenzaldehyde which is then either oxidized to 2-chlorobenzoic acid for subsequent glycine conjugation, or reduced to 2-chlorobenzyl alcohol for ultimate excretion as 2-chlorobenzyl acetyl cysteine or 1-O-(2-chlorobenzyl) glucuronic acid. Malononitrile is converted to thiocyanate via the formation of cyanide.

Animals↗
PubMed1986

The in vitro penetration and distribution of T-2 toxin through human skin.

The penetration and distribution of T-2 toxin in excised human abdominal skin has been determined for a dose range of 1.0-2.6 micrograms/cm2 skin using an ethanol vehicle and a saline receptor solution. In all cases the overall percentage penetration of T-2 after 48 h was low, the greatest amounts of toxin being present in the stratum corneum with less in the epidermis and relatively little in the dermis. Vehicle: skin partition coefficients support this finding. Neither penetration nor distribution were changed by a rabbit serum receptor solution. Electron micrographs showed that at 1.8 micrograms/cm2 and above the contents of the intercellular space are leached out to leave the integument as a porous membrane. The distribution of T-2 within the skin after 48 h would suggest that for doses up to 2.6 micrograms/cm2 the irritative and inflammatory effects on the skin would be of more immediate concern than would systemic toxicity.

Diffusion↗
PubMed1986

Acute toxicity of T2 mycotoxin to the guinea-pig by inhalation and subcutaneous routes.

The acute inhalation and subcutaneous toxicity of T2 mycotoxin has been investigated in guinea-pigs. The toxicity by the two routes was quantitatively and qualitatively similar. The LCt50 was 5749 mg min m-3 and the subcutaneous LD50 1-2 mg kg-1. Histological changes in the decedents which were similar by both routes of administration were most marked in the lymphoreticular system but also occurred in the gut. Lymphocytolysis and phagocytosis occurred in both the cortex of the thymus and of the lymph nodes. Lymph nodes were more severely affected in the decedents among the animals dosed with T2 by the subcutaneous route. The small intestine exhibited dead and dying cells throughout the lamina propria after T2 by either route.

Aerosols↗
PubMed1983

The effect of sensory irritants on phagocytosis by pulmonary macrophages.

The phagocytosis of Staphylococcus epidermis by rabbit alveolar macrophages was measured in the absence or presence of a series of sensory irritants. The phagocytic index was determined in the presence of the sensory irritant dibenzoxazepine and 10 of its derivatives. All of the compounds tested inhibited phagocytosis to some extent. Dibenzoxazepine was the most potent inhibitor and the 1-chloro and 2-chloro derivatives were the least potent. With all the compounds tested, the inhibition of phagocytosis was dose dependent. The degree of inhibition of phagocytosis was not correlated with either the nature or the position of the substituent groups on the dibenzoxazepine molecule. There was no discernible relationship between the inhibition of phagocytosis and the irritancy of the compounds tested.

Animals↗
PubMed1983

The fate of dibenz[b,f]-1,4-oxazepine (CR) in the rat, rhesus monkey and guinea-pig. Part I. Metabolism in vivo.

The fate of dibenz[b,f]-1,4-[11(14)-C]oxazepine (CR) in rats, rhesus monkey and guinea-pig and in isolated perfused rat livers has been examined. 14C-CR was administered to rats at doses from 1.56 to 3470 mumol/kg and irrespective of dose or route of administration most (59-93%) was eliminated in the urine as primarily the sulphates of the 7-, 4- and 9-hydroxylated 10,11-dihydrodibenz[b,f]-1,4-oxazepine-11(10H)-one. In blood, both in vivo and in liver perfusates, CR concentrations decreased biphasically to be replaced initially with CR-lactam (dihydrodibenz[b,f]-1,4-oxazepine-11(10H)-one), followed by the sulphates of the 7-, 4- and 9-hydroxylactams. The rate of disappearance of CR in liver perfusates was slower than in vivo. Bile contained only small amounts of sulphate conjugates and significant amounts of conjugated 2-amino-2'-hydroxymethyldiphenyl ether (amino alcohol). This was not identified in the urine or blood of rats. Preliminary studies in rhesus monkey and the guinea-pig show similar excretory patterns and metabolites. However, only free hydroxylactams were isolated from monkey urine and traces of the amino alcohol were detected in guinea-pig urine. Whole-body autoradiography of mice confirm the rapid disappearance of CR from blood into heart, liver, kidneys and small intestine with evidence of biliary excretion. It is consistent with the rat studies showing the rapid absorption of a highly lipophilic compound undergoing hepatic metabolism, biliary secretion, enterohepatic recirculation and renal excretion.

Animals↗
PubMed1983

The fate of dibenz[b,f]-1,4-oxazepine (CR) in the rat. Part II. Metabolism in vitro.

CR (dibenz[b,f]-1,4-oxazepine) is metabolized by rat liver 105 000 g supernatant fractions by (a) ring opening and reduction to 2-amino-2'-hydroxymethyldiphenyl ether and (b) oxidation at C11 to give a cyclic lactam. Reaction (a) is NADPH-dependent, decreased by dialysis and methylene blue, whereas reaction (b) is heat-resistant, inactivated by dialysis, inhibited by CN-, p-chloromercuribenzoate, amytal and menadione, and stimulated by methylene blue, phenazine methosulphate and 2,6-dichlorophenol indophenol. Reaction (a) is similar to that of aldehyde reductases (E.C.1.1.1.2) and reaction (b) to that of molybdenum hydroxylases (E.C.1.2.3.1). Reaction (a) is also catalysed by an NADH-dependent enzyme in liver microsomes and subsequent hydroxylation of the lactam also occurs in this cell fraction. Some extrahepatic metabolism of CR occurs via the same routes in kidney, small intestine and lung, though the yield is limited. Digestive gland extract of Helix pomatia converts CR to its lactam in significant amounts. The metabolism of CR in vitro is similar to that predicted from observations in vivo.

Animals↗
PubMed1983

The fate of dibenz[b,f]-1,4-oxazepine (CR) in the rat. Part III. The intermediary metabolites.

The fates of several intermediates of dibenz[b,f]-1,4-oxazepine (CR) metabolism in vivo and in vitro in rats have been examined to establish the metabolism and excretory sequence of CR. The ring-opened 2-amino 2'-hydroxymethyldiphenyl ether (amino alcohol) added to isolated perfused rat liver was rapidly cleared in bile as a mixture of highly polar conjugates, whereas the major route of excretion in vivo was as the 4-, 7- and 9-hydroxylactam sulphates in urine. The lactam of CR was eliminated exclusively in urine giving the same products as obtained for CR, but the distribution of metabolites of the C10-C11 dihydro derivative of CR was unlike that of the parent compound indicating that it occupies only a peripheral role in the fate of CR in vivo. A mixture of 7-, 4- and 9-hydroxylactams derived from the enzymic hydrolysis of urinary sulphates was rapidly removed from blood, sulphated and secreted as sulphates into blood both in vivo and in isolated perfused liver. Little biliary excretion occurred. When the urinary sulphates of the hydroxy lactams were administered i.v. to rats, 70% was eliminated in urine within 1 h; however, if the kidneys were ligated biliary excretion of sulphate was higher (58% in 5 h). After intraduodenal administration of the biliary conjugates of CR metabolism, all of the dose was resorbed to be re-secreted in bile or excreted as sulphates in urine. These studies confirm that the major metabolic fate of CR in the rat is oxidation to lactam, followed by ring hydroxylation, sulphation and urinary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

The relationship between binding to cytochrome P-450 and metabolism of n-alkyl carbamates in isolated rat hepatocytes.

The binding constants of an homologous series of n-alkyl (C2-C10) carbamates (see formula in text) to the cytochrome P-450 of suspensions of isolated, viable rat hepatocytes have been measured. All the carbamates except ethyl and propyl carbamate produced type I difference spectra and their binding affinities (1/Ks) were found to be directly dependent upon their lipophilicity. These binding affinities were similar to those determined in rat liver microsomes. Maximum development of the binding spectrum in hepatocytes was always within one second of the addition of each carbamate, indicating that for these carbamates membrane permeability was not rate limiting for access to, and metabolism by, cytochrome P-450 and that much of the cells' cytochrome P-450 was unoccupied by endogenous substrates. Th major metabolites of C4-C8 carbamates were unconjugated omega-1 oxidation products. Below hexyl carbamate only the omega-1 hydroxylated metabolite was observed but for the more lipophilic carbamates the keto metabolite was also a major product. The same products were found in blood after i.p. dosing of rats with hexyl carbamate. A direct relationship was observed between the affinity constant of the carbamate for cytochrome P-450 and the total rate of oxidative metabolism in the omega-1 position. Hydrolysis of the carbamate group was a minor metabolic pathway in contrast to the in vivo situation.

Animals↗
PubMed1982

The relationship between chemical structure and the in vivo metabolism of an homologous series of n-alkyl carbamates.

The metabolism and pharmacokinetics of carbonyl [14C] labelled ethyl, n-butyl, n-hexyl and n-octyl carbamates has been examined in rats after oral and intravenous administration. Hydrolysis of the carbamate group was a major metabolic fate, particularly of the more water soluble carbamates. Conversely, with increasing lipophilicity increasing amounts of omega-1 oxidation products were found both in plasma and urine. The plasma pharmacokinetic data could not be explained by a simple bi-exponential model, ethyl carbamate in particular showing unexpectedly persistent blood levels. A model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential features of this model are that carbamate is thought not to be in equilibrium between the peripheral and central compartment and that hydrolytic metabolism takes place in the peripheral compartment while oxidative metabolism to urinary metabolites occurs in the central compartment.

Animals↗
PubMed1979

Rapid absorption from the urinary bladder of a series of n-alkyl carbamates: a route for the recirculation of drugs.

1 The rate of loss of a series of n-alkyl carbamates from the lumen of the urinary bladders of female rats has been studied. 2 The rate of loss obeys first order kinetics and was not affected by water flux across the bladder wall nor by binding of the carbamates to it. 3 The rate of loss of octyl carbamate was reduced by about 76% by the presence of 5% Tween 80. Histological evidence indicates that this may be due to the formation of a thin luminal lining which may be adsorbed Tween 80 or mucopolysaccharide material. 4 The absorption rate of the carbamates was limited by their hydrophilicity but reached a plateau for the more lipophilic homologues with a half life for loss of approximately 10 min. 5 The implications of these results with regard to the recirculation of unmetabolized drugs and hydrolysed conjugates of drugs, the systemic absorption of intravesically applied cancer chemotherapeutic agents and bladder wall permeability to carcinogens are discussed.

Absorption↗
PubMed1978

The absorption of aliphatic carbamates from the rat colon.

The colonic absorptio n of a series of aliphatic carbamates has been studied using an in situ preparation in the rat. The absorption process appeared to be passive and no metabolism by the colon membrane was detected. A linear correlation between the logarithms of the absorption rate constants and apparent partition coefficients was found. The absorption rates were not affected by concurrent water flux.

Animals↗
PubMed1976

Gastrointestinal absorption of carbenoxolone in the rat determined in vitro and in situ: deviations from the pH-partition hypothesis.

The absorption of [14C] carbenoxolone from everted rat ileum in vitro and from rat stomach and ileum in situ has been examined. The rate of its mucosal to serosal transfer in vitro increases as pH increases from 5 to 8 whereas the amount bound to ileum tissue decreases with increased pH; absorption closely parallels the drug's solubility. The uptake of carbenoxolone in situ is bi-exponential and the rate constants for the two processes, have been calculated. Absorption in situ, and biliary excretion, of the drug increases with increasing pH from 5.0 to 7.4. Tissue binding to the ileum in situ is not dependent on pH except below pH 5.0 when extensive tissue accumulation of carbenoxolone occurs because of its low solubility. Tissue binding to the stomach increases markedly with decrease of pH from 7.4 to 6.5 and at pH 6.5 is 80 times greater than binding to the intestine. The rate of absorption from the stomach, at pH 6.5-7.4, was much less than that from the intestine in situ. When allowance is made for the binding of carbenoxolone to the stomach, contrary to the pH-partition hypothesis, correlation is apparent between its absorption and the amount present in the ionized form.

Animals↗