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Biomedical subjects

J L Plummer

Publications and source records attributed to J L Plummer.

At least 91 records · Page 5Linked to original sources
PubMed1985

Hepatic and renal effects of prolonged exposure of rats to 50 p.p.m. methoxyflurane.

Male Fischer 344 rats were exposed to air or to 50 p.p.m. methoxyflurane vapour for a period of 14 weeks. At the end of this period, half of the rats in each group were killed; the remainder breathed air only for a further four weeks (recovery period) before being killed. During the exposure period, growth of the methoxyflurane-exposed rats was markedly depressed, though food consumption was similar in the two groups. Both water consumption and urine volume were increased by methoxyflurane, possibly due to the nephrotoxic effect of fluoride, the concentration of which exceeded 50 micromolar in the sera of all exposed rats. At the end of the exposure period, livers of all exposed rats, but no controls, showed focal hepatocellular degeneration and necrosis, and evidence of liver cell regeneration. Fatty change was prominent. During the recovery period, water consumption and urine volumes returned to near-normal levels. At the end of the recovery period, focal necrosis was still observed in the livers, although fatty change was no longer present. No histological abnormalities were observed in the kidneys of any rats.

Animals↗
PubMed1985

Sex differences in halothane metabolism and hepatotoxicity in a rat model.

This study was designed to investigate sex differences in halothane metabolism and hepatotoxicity in the hypoxic rat model. Phenobarbital-induced male and female rats were anesthetized with 1% halothane in 14% oxygen for two hours. Female rats were found to metabolize halothane by the oxidative pathway to a similar extent as males, but the extent of metabolism by the reductive pathway was less in females. All male rats exposed under these conditions developed confluent centrilobular hepatic necrosis. Females were less susceptible than males to the hepatotoxic effect of halothane, with responses ranging from no hepatic injury to confluent centrilobular necrosis limited to within a few cells of the central veins. This lesser susceptibility was not, however, solely due to the lesser extent of reductive metabolism in females, as lowering the inspired oxygen concentration to 12% increased the extent of reductive metabolism but did not increase the severity of the hepatic injury.

Alanine Transaminase↗
PubMed1984

Reductive metabolism of halothane in children.

The volatile halothane metabolites, 2-chloro-1,1,1,-trifluoroethane and 2-chloro-1,1-difluoroethylene, were identified in the exhaled breath of ten children during halothane anaesthesia. Although there was considerable variation among children in the concentration and time-course of metabolite exhalation, exhaled concentrations of these metabolites were of a similar magnitude to those reported in adults. This result suggests that the lower incidence of halothane hepatitis in children compared with adults is not due to a poor ability to metabolise halothane by the reductive pathway.

Anesthesia, Inhalation↗
PubMed1983

Hepatic injury in rats due to prolonged sub-anaesthetic halothane exposure.

Fischer-344 rats of both sexes were exposed to halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) at a concentration of 50 p.p.m. for twelve weeks. During the course of the experiment, weight gain of both sexes was depressed and serum alanine aminotransferase activities were elevated, compared to control animals. The temporal pattern of alanine aminotransferase elevation differed between the sexes. After 12 weeks of exposure, liver/body weight ratio was increased in both sexes, and pathological changes were observed in their livers. Livers of all halothane-exposed animals showed focal liver cell necrosis, considerable lobular disarray and occasional mitoses. Many liver cells showed fatty change. None of these changes were observed in any control animals. These results indicate that prolonged exposure to a low concentration of halothane caused mild liver damage with regeneration. This finding may be of significance to humans occupationally exposed to halothane.

Aerosols↗
PubMed1983

Anaesthesia and the kidney.

Applied anatomy and physiology of the kidney are briefly reviewed. This includes an account of renal blood flow, glomerular filtration rate, juxtaglomerular apparatus, renal autoregulation and intra-renal blood flow distribution, tubular transport mechanisms, solute handling in proximal tubule, function of loop of Henle and distal tubule system. This section concludes with a summary of changes in tubule fluid along the length of the nephron. Acute effects of anaesthesia are reviewed in detail. Indirect effects include those on circulatory and sympathetic nervous systems, autoregulation, endocrine systems such as those involving anti-diuretic hormone, adrenaline and noradrenaline, renin-angiotensin and aldosterone. Direct effects of anaesthesia on renal function have now been confirmed both in vitro and in vivo. Delayed direct nephrotoxicity of anaesthetics relates predominantly to methoxyflurane (MOF) and its metabolism to inorganic fluoride. Other factors are MOF dose, genetics, age, enzyme induction, obesity, other nephrotoxic drugs. Clinical implications are presented. Enflurane nephrotoxicity is rare but aetiologic factors are similar to the foregoing. Isoflurane and halothane are not nephrotoxic. A consideration of the influence of anaesthetic management on the incidence and severity of postoperative acute renal failure concludes the review.

Anesthesia↗
PubMed1982

Free radical formation in vivo and hepatotoxicity due to anesthesia with halothane.

In vivo studies were undertaken to determine whether free radical formation in the liver during administration of various halogenated anesthetics is associated with hepatotoxicity of these agents in an animal model. In addition to the anesthetics halothane, enflurane, and isoflurane, carbon tetrachloride was studied as an example of a hepatotoxic halogenated compound acting by a free radical mechanism. Free radicals were trapped in vivo during anesthesia as stable adducts using the spin trap, alpha-phenyl-t-butyl nitrone. These adducts were extracted from the liver and studied by electron spin resonance spectrometry. Free radicals were detected after administration of halothane or carbon tetrachloride, compounds which were hepatotoxic under the conditions of the experiment, but were not found after anesthesia induced with enflurane or isoflurane, anesthetics which were not hepatotoxic under identical conditions. The free radical trapped after alpha-phenyl-t-butyl nitrone treatment of halothane-anesthetized rats appeared to be a metabolic intermediate of halothane.

Animals↗
PubMed1981

Metabolism of benzo(a)pyrene and benzo(a)pyrene 4,5-oxide in rabbit lung.

For several years our laboratory has been investigating the biotransformation of various environmental pollutants by lung. Studies have been performed with pulmonary subcellular fractions, purified monooxygenase and glutathione transferase enzymes, and preparations having intact cellular structure including the isolated perfused lung and cell fractions enriched in alveolar macrophages, Clara cells and alveolar type II cells. Collectively, these investigations have identified several metabolic factors which may contribute to the pulmonary toxicity mediated by certain polycyclic aromatic hydrocarbons (PAH). First, although lung has low overall cytochrome P-450-dependent monooxygenase activity for many substrates, relative to liver, this activity is localized in only a few cell types and specific activity in certain cell types, such as the non-ciliated bronchiolar epithelial (Clara) cell, can be high. Second, oxidative metabolites of benzo(a)pyrene tend to accumulate in pulmonary tissue due, at least in part, to the low ability of lung (relative to liver) to conjugate and detoxify phenolic, dihydrodiol and epoxide metabolites. Thus, products such as benzo(a)pyrene 7,8-dihydrodiol are available for further cytochrome P-450-dependent oxidation to ultimate carcinogens and cytotoxins. Moreover, the lung is efficient in removing benzo(a)pyrene 4,5-oxide and presumably other oxidized PAH metabolites, from the bloodstream. Consequently, the uptake of relatively stable electrophilic metabolites released by the liver may also contribute to pulmonary toxicity.

Animals↗
PubMed1979

Benzo(a)pyrene oxidation, conjugation and disposition in the isolated perfused rabbit lung: role of the glutathione S-transferases.

The isolated perfused rabbit lung metabolised 7--11 % of 20 mumol of [14C]-benzo(a)pyrene added in the perfusion medium in 1 h. The major metabolite formed was 3-hydroxybenzo(a)pyrene, both free (30--40 % of the total metabolites) and conjugated (4 % of total metabolites). Quinones comprised 15 % of the total and metabolism at the 9, 10 position accounted for a further 10 %. Forty per cent of the water-soluble metabolites was chromatographically identical to the glutathione conjugate of benzo(a)pyrene 4,5-oxide. Sulphate and glucuronide conjugates were formed in small but detectable amounts, principally from phenols, but also from dihydrodiols. After 1 h the more water-soluble conjugates had diffused from the lung into the perfusion medium, but the majority (60--90 %) of the metabolic products were still concentrated within the lung. The lung's limited ability to conjugate its major metabolites of benzo(a)pyrene with sulphuric or glucuronic acid, coupled with slow elimination of the products formed, particularly dihydrodiols may contribute to the susceptibility of this organ to polycyclic aromatic hydrocarbon-induced carcinogenesis.

Animals↗
PubMed1978

The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat.

Curcumin labelled with deuterium and tritium was prepared. Oral and intraperitoneal doses of [3H]curcumin led to the faecal excretion of most of the radioactivity. 2. Intravenous and intraperitoneal doses of [3H]curcumin were well excreted in the bile of cannulated rats. 3. The major biliary metabolites were glucuronides of tetrahydrocurcumin and hexahydrocurcumin. A minor biliary metabolite was dihydroferulic acid together with traces of ferulic acid. Metabolites were identified using chemical ionization mass spectrometry.

Animals↗
PubMedDate not supplied

The pathology of liver injury induced by the chronic administration of alcohol and 'low-dose' carbon tetrachloride in Porton rats.

We have previously established a model for micronodular cirrhosis by feeding Wistar rats alcohol, in the Lieber-DeCarli liquid diet, and exposing them to 'low-dose' carbon tetrachloride (CCl4) vapour for 10 weeks. This study reports the spectrum of liver pathology seen in male Porton rats exposed to 'low-dose' CCl4 vapour 5 nights/week, 6 h/night while being fed alcohol (300 kcal/L) in the Lieber-DeCarli diet. Micronodular cirrhosis developed in all animals after 5-7 weeks of treatment. The simultaneous administration of silymarin, a putative hepatoprotective agent, in the liquid diet, did not alleviate or prevent the chronic liver injury. The histopathological features of the liver injury are described, with particular emphasis on the presence of small epithelial cells ('progenitor or stem cell'), which appear to be playing a role in liver regeneration.

Administration, Oral↗
PubMedDate not supplied

Metabolism and biliary excretion of benzo[a]pyrene 4,5-oxide in the rat.

The excretion and biliary metabolites of intravenously administered benzo[a]pyrene 4,5-oxide were studied in the rat at two dose levels. After administration of 4.5 or 0.47 mumol, half of the dose was excreted in the bile in 60 min. Biliary metabolites were separated by reverse-phase high-pressure liquid chromatography and identified by cochromatography with biosynthetic standards, beta-glucuronidase hydrolysis, ultraviolet spectrophotometry and, in the case of the thioether conjugates, identification of the constituent amino acids. The major biliary metabolite was a mixture of isomeric glutathione conjugates. Some cysteine conjugate was also present, but no cysteinylglycine conjugate was detected. Hydration to transbenzo[a]pyrene-4,5-dihydrodiol followed by glucuronidation was also a quantitatively important metabolic pathway. Although benzo[a]pyrene-4,5-dihydrodiol glucuronide was more readily excreted by the liver than was benzo[a]pyrene 4,5-oxide:glutathione conjugate, the rate of glucuronidation of the dihydrodiol was low, resulting in its accumulation in the liver and possible release into the circulation. Therefore, the glutathione S-transferases may provide a more efficient mechanism for the removal of benzo[a]pyrene 4,5-oxide from the body than is provided by expoxide hydrolase.

Animals↗