Biomedical subjects

G L Plaa

Publications and source records attributed to G L Plaa.

172 records · Page 10Linked to original sources

PubMedDate not supplied

Biliary excretion in Sprague-Dawley and Gunn rats during manganese-bilirubin-induced cholestasis.

We previously showed that alterations of the bile canalicular membrane are likely to occur following a cholestatic regimen composed sequentially of manganese and bilirubin. The present study was designed primarily to investigate the biliary excretion of organic bile constituents following administration of the manganese-bilirubin combination. Experiments in hyperbilirubinemic Gunn rats were also performed to determine whether the unconjugated or the conjugated form of bilirubin is involved in this cholestatic interaction. Male Sprague-Dawley rats and male homozygous Gunn rats were given the following (i.v.): (a) manganese (4.5 mg per kg); (b) unconjugated bilirubin (25 mg per kg); (c) bilirubin ditaurate (38 mg per kg); (d) manganese-unconjugated bilirubin, or (e) manganese-bilirubin ditaurate. Bile flow was measured and bile was analyzed for manganese, total bilirubin, bile salts, cholesterol and phospholipid content. The results show that: (i) manganese-unconjugated bilirubin treatment caused about a 50% reduction in bile flow in Sprague-Dawley rats, whereas in Gunn rats the manganese-bilirubin ditaurate treatment resulted in about a 75% reduction, and (ii) in both strains, bile salt excretion was not appreciably modified during the cholestatic phase, as biliary bile salt concentration increased. The results suggest that although important differences regarding the form of bilirubin apparently exist, unconjugated bilirubin could be implicated in the cholestatic interaction in both strains of rats. Manganese-bilirubin-induced cholestasis is not related to a defect in bile salt excretion. The latter supports our contention that diminished canalicular membrane permeability to water is likely to be a key factor in this form of experimental cholestasis.

Animals↗

PubMedDate not supplied

Pharmacodynamic and metabolic interactions between ethanol and two industrial solvents (methyl n-butyl ketone and methyl isobutyl ketone) and their principal metabolites in mice.

MnBK and MiBK prolong the duration of ketamine-, pentobarbital-, thiopental- and ethanol-induced loss of righting reflex (LRR) in mice. In equimolar doses, (5 mmol/kg i.p.), both isomers were equipotent with respect to the enhancement of ketamine-, pentobarbital-, and thiopental-induced LRR. However, MnBK was significantly more effective (twice as effective) than its isomer with respect to enhancing ethanol-induced LRR. An attempt to explain the difference in effectiveness between the two isomers was carried out. The effects of both ketones and their principal metabolites, (2-hexanol (2-HOL), 2,5-hexanedione (2,5-HD), 4-methyl-2-pentanol (4-MPOL) and 4-hydroxy 4-methyl-2-pentanone (HMP)) on ethanol-induced LRR and ethanol elimination were studied in mice. The ketones and their metabolites were dissolved in corn oil and injected intraperitoneally 30 min before 4 g/kg ethanol for LRR and 2 g/kg for ethanol elimination. Ethanol-induced LRR was significantly prolonged by the following dosages (mmol/kg), MnBK, 5; MiBK, 5; 2-HOL, 2.5; 4-MPOL, 2.5; and HMP, 2.5; 2,5-HD, 2.5, however exerted no effect. Concentrations of ethanol in blood or brain upon return of the righting reflex were similar in solvent-treated and control animals. The mean elimination rate of ethanol was slower in groups pretreated with MnBK or 2-HOL as compared to control animals. Ethanol elimination in animals pretreated with MiBK, HMP, 4-MPOL, or 2,5-HD was similar to that in control animals. These ketones are known to have some central depressant action on their own. This by itself could lead to prolongation of ethanol-induced LRR. However, MnBK, as well as one of its principal metabolites, (2-HOL), markedly reduced ethanol elimination. This could explain the observation that MnBK has a greater potentiating effect on ethanol-induced LRR that its isomer, MiBK, which does not affect ethanol elimination.

Animals↗

PubMedDate not supplied

Fractional hepatic localization of 14CHCl3 in mice and rats treated with chlordecone or mirex.

In rodents chlordecone, but not mirex, a nonketonic structural analog, significantly augments CHCl3-induced liver damage, at least in part, by increasing CHCl3 bioactivation. To determine whether the fractional distribution of CHCl3 was altered in chlordecone-pretreated animals, the irreversible binding of 14CHCl3 to various liver constituents (a measure of CHCl3 bioactivation) was examined in vivo in mice and rats. Chlordecone, but not mirex, increased both total and irreversibly bound 14CHCl3; furthermore, changes in the 14C localization between lipid, protein and acid-soluble fractions were noted. Thus, the results suggest that differences exist between chlordecone and mirex with respect to their capacity to increase the quantity of CHCl3-derived reactive metabolite and the eventual distribution of reactive metabolite.

Animals↗

PubMedDate not supplied

Relationships between histological and functional indices of acute chemically induced nephrotoxicity.

Acute renal injury was produced in rats with K2Cr2O7 (5-40 mg/kg, sc) HgCl2 (0.5-5.0 mg/kg, sc) or cephaloridine (0.5-3.0 g/kg, sc). Histological (percentage of normal, degenerated or necrotic cells) and functional indices (relative kidney weight, renal cortical slice accumulation of organic ions, and blood urea nitrogen content) were evaluated 48 hours later. The relative sensitivity of each of these indices was determined for each nephrotoxicant. Renal cortical accumulation of organic ions appeared to be the most sensitive of the functional parameters. A quantitative histological evaluation was found to be as sensitive an indicator of nephrotoxicity as organic ion accumulation. Alterations in each of the functional indices were significantly correlated with changes in renal histology.

Animals↗

PubMedDate not supplied

Simultaneous high-performance liquid chromatographic analysis of hippuric acid and ortho-, meta-, and para-methylhippuric acids in urine.

A high-performance liquid chromatographic assay for the simultaneous analysis of hippuric and methylhippuric acids in urine is described. Compounds are first extracted from acidified urines after addition of o-methylbenzoylalanine (internal standard), using methyl-t-butyl ether. The organic phase is evaporated under nitrogen flow and the residue dissolved in the mobile phase which consisted of 91% potassium phosphate buffer (12.0mM, pH: 2.0), 4.5% methanol, and 4.5% tetrahydrofuran. The method described allows complete separation of meta- and para-methylhippuric acids in less than 20 min using a stainless steel column packed with octadecyl-dimethysilyl silica. The authors used this method to determine the urinary excretion of hippuric and methylhippuric acids in rabbits following exposure to a mixture of toluene and isomers of xylene. Data indicated that under the actual experimental conditions of exposure o-xylene is excreted to a lesser extent as a methylhippuric acid than the meta- and para-xylenes.

Animals↗

PubMedDate not supplied