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G L Plaa

Publications and source records attributed to G L Plaa.

At least 55 records · Page 3Linked to original sources
PubMed1990

Dose-dependent cytotoxicity of chlorinated hydrocarbons in isolated rat hepatocytes.

The aim was to determine if isolated suspended hepatocytes could differentiate between the effects of four chlorinated hydrocarbons that are hepatotoxic in vivo and four that are not. Membrane integrity was assessed by measuring alanine aminotransferase (ALT) release after 30- to 180-min incubations in vitro. From the results, the chlorinated hydrocarbons fell into three groups: tetrachloroethylene and 1,1,2,2-tetrachloroethane were the most potent cytotoxicants; CCl4, 1,1,2-trichloroethane, and trichloroethylene exhibited intermediate cytotoxicity; and low cytotoxicity was observed with CHCl3, 1,1,1-trichloroethane, and 1,1-dichloroethylene. Cytotoxicity ranking correlated poorly with the reported in vivo hepatotoxicity of these agents. The effect of adding SKF-525A on the cytotoxicity of tetrachloroethylene and CCl4 was also assessed. In addition, hepatocytes from rats pretreated with 2,5-hexanedione were used to determine if they were more susceptible to the effects of CHCl3, CCl4, or tetrachloroethylene. SKF-525A decreased the cytotoxicity of both CCl4 and tetrachloroethylene, whereas pretreatment with 2,5-hexanedione enhanced their effect. The effects of both SKF-525A and 2,5-hexanedione on CCl4 in vitro are consistent with in vivo findings. However, tetrachloroethylene is not hepatotoxic in vivo, suggesting that SKF-525A might act by stabilizing plasma membranes rendering the hepatocyte more resistant to lysis. Overall, the results cast doubts on the use of ALT release from isolated hepatocytes as an appropriate in vitro model for assessing hepatotoxic properties of chlorinated hydrocarbons.

Alanine Transaminase↗
PubMed1989

Effects of acetone and methyl n-butyl ketone on hepatic mixed-function oxidase.

The administration of ketones potentiates CCl4 hepatotoxicity; however, the potencies of the ketones differ. The aim of the present study was to assess potential differences between acetone and methyl n-butyl ketone (MnBK) on cytochrome P-450. The effects of single and repetitive doses of acetone and MnBK were determined in male rats by estimating the rate of metabolite formation of three substrates and the hepatic content of cytochrome P-450. A single treatment with acetone (13.5 mmol/kg or greater) enhanced the oxidation of aniline and 7-ethoxycoumarin, whereas repetitive treatments also increased aminopyrine demethylation and cytochrome P-450 content. Single and repetitive treatments of MnBK (15 mmol/kg) augmented the oxidation of all three substrates and increased cytochrome P-450 content. The effects of the ketones on cytochrome P-450 isozymes were characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Acetone and MnBK increased the 52.1 and 54.1 kD forms and, in addition, MnBK tended to increase the 50.6 kD species. The data indicate that ketones differ in the type of isozymes induced and in the degree of induction. The higher potency of MnBK, compared to acetone, is probably associated with the fact that MnBK affects a greater number of isozymes than acetone.

Acetone↗
PubMed1989

Effect of inhibition of protein synthesis on cholestasis induced by taurolithocholate, lithocholate, and a manganese-bilirubin combination in the rat.

Taurolithocholate, lithocholate, and a manganese-bilirubin combination produced a rapid reduction in bile flow after i.v. injection in the rat. The effect was diminished or blocked completely by pretreating the animals with cycloheximide or ethionine, known inhibitors of protein synthesis. The injection sequence and time period between administration of the inhibitor of protein synthesis and the cholestatic agent influenced the degree to which they modulated the cholestatic effect. The results indicate that uninterrupted protein synthesis is required for the expression of maximal reduction of bile flow by taurolithocholate, lithocholate, and a manganese-bilirubin combination.

Animals↗
PubMed1989

Pharmacological and metabolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice.

Methyl n-butyl ketone (MnBK), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone are widely used industrial solvents to which certain groups of workers are exposed. Pharmacological and metabolic interactions between these solvents and ethanol were explored in male CD-1 mice. The effects of these solvents on the duration of ethanol-induced loss of righting reflex and on ethanol elimination in mice were studied. The solvents were dissolved in corn oil and injected intraperitoneally 30 min before ethanol 4 g/kg ip. The four solvents prolonged significantly the duration of ethanol-induced loss of righting reflex when given in the following doses (mmol/kg): MnBK, 3.75 and 5; MIBK, 5; MEK, 5 and 10, acetone, 20 and 40. This prolongation was dose related and increased as the dose of the solvent was increased. The concentrations of ethanol in blood or brain on return of the righting reflex were similar in solvent-treated and control animals, with the exception of the group of mice treated with 40 mmol/kg acetone in which the ethanol concentrations were significantly lower than in control animals. The mean elimination rate of ethanol was markedly reduced in mice treated with MnBK 5 mmol/kg, MEK 15 mmol/kg, and acetone 40 mmol/kg. All four solvents reduced the activity of mouse liver alcohol dehydrogenase in vitro. It is concluded that enhancement of the ethanol-induced loss of righting reflex by these solvents in mice is well correlated to reduced elimination rate of ethanol.

Acetone↗
PubMed1988

Potentiation of CCl4-induced liver injury by ketonic and ketogenic compounds: role of the CCl4 dose.

Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well-known phenomenon. The importance of the CCl4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma ALT activity and bilirubin concentrations after CCl4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The MED values were determined from the plasma ALT data. Results showed that when the CCl4 dosage was increased from 0.01 to 0.10 ml/kg, the MED of each potentiator decreased 10-fold. For a given potentiator, the product of the CCl4 dosage (H, "hepatotoxicant") by the corresponding MED value (P, "potentiator") remained the same in this range of CCL4 dosages. The severity of the liver injury was similar. These findings suggest that a given level of liver injury induced by a ketone/haloalkane combination could be evaluated on the basis of the [P X H] product.

Animals↗
PubMed1988

Methyl isobutyl ketone metabolites and potentiation of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone.

Methyl isobutyl ketone (MIBK) has recently been shown to potentiate the cholestasis induced by manganese-bilirubin (Mn-BR) or manganese (Mn) in rats. In this study, we investigated the effect of 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK), two major metabolites of MIBK, on these models of cholestasis. Dosages varying from 1.88 to 15 mmol/kg 4MPOL or 4-OHMIBK were administered once, 18 hr prior to the administration of a cholestatic Mn-BR combination. The cholestatic effect of the manganese-bilirubin combination was enhanced with dosages of 4MPOL of 3.75 mmol/kg and larger. On the other hand, dosages smaller than 15 mmol/kg of 4-OHMIBK did not potentiate the Mn-BR cholestasis. Daily pretreatment for 3 days resulted in an increased response to the cholestatic challenges of either Mn-BR or Mn alone. 4MPOL administered repetitively was a better potentiator than 4-OHMIBK with the Mn-BR model of cholestasis. However, with Mn alone, 4-OHMIBK proved to be more effective. 4MPOL and 4-OHMIBK per se were devoid of cholestatic properties, since the bile flow measured prior to the cholestatic challenge was not decreased and in some cases was significantly greater than that of vehicle-pretreated animals. These results show that MIBK metabolites can potentiate the cholestatic form of hepatotoxicity.

Animals↗
PubMed1988

Experimental evaluation of haloalkanes and liver injury.

Potentiation of haloalkane-induced hepatotoxicity by ketones and ketogenic substances is used to illustrate questions that are raised when considering biological interactions involving toxicants. The following characteristics are considered: The effect of the potentiator (ketone or ketogenic agent) on the dose-response characteristics of the haloalkane toxicant; the recovery process of the potentiated tissue injury; dose-response characteristics of the potentiators (minimally effective dosages); correlation of the potentiation with blood levels of the potentiator (threshold concentrations). The relative specificity of the haloalkanes for interaction are discussed, as well as the potentiation of various forms of hepatic injury (acute, chronic, necrogenic, and cholestatic). Enhanced bioactivation of the haloalkane toxicant is a major mechanism of action for the potentiator; other possible contributing mechanisms, however, require consideration. Mixtures of haloalkanes, leading to enhanced liver injury, can also be potentiated by ketones.

Animals↗
PubMed1988

Assessment of the minimal effective dose of acetone for potentiation of the hepatotoxicity induced by trichloroethylene-carbon tetrachloride mixtures.

Administration of acetone to rats in amounts larger than or equal to a minimal effective dosage (MED) is known to potentiate the severity of the liver damage produced by CCl4 alone. It has been reported that CCl4-induced hepatotoxicity is also enhanced by the previous administration of trichloroethylene (TCE). In addition, TCE-CCl4 mixture-induced liver injury is potentiated by acetone. The present study was undertaken to determine if the acetone MED is decreased when the haloalkane challenge is a mixture of TCE-CCl4 instead of CCl4 alone. The effect of varying mixture compositions was also evaluated. In a first series of experiments, male Sprague-Dawley rats received corn oil or acetone (0.05-0.25 ml/kg, po); 18 hr later, they received an ip injection of either CCl4 (0.1 ml/kg) or [TCE (0.25 ml/kg)-CCl4 (0.1 ml/kg)]. In a second series, rats received corn oil or acetone (0.75 ml/kg), and were challenged with TCE (1.5 ml/kg), CCl4 (0.25 ml/kg), or a mixture of TCE-CCl4, where TCE and CCl4 dosages were equal to 25-75%, 50-50%, and 75-25%, respectively, of those used for the administration of the solvents alone. In both series, rats were killed 24 hr after the haloalkane challenge. Liver injury was assessed biochemically (plasma ALT activities and bilirubin concentrations) and morphologically. When TCE was added to a solution of CCl4, smaller doses of CCl4 were required to produce equally severe liver injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗
PubMed1987

Potentiation by methyl isobutyl ketone of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone.

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK). In a previous study, MIBK was shown to potentiate the cholestasis induced by taurolithocholate in rats. We investigated the possibility that this ketone could potentiate the cholestasis induced by a combination of manganese and bilirubin (Mn-BR) or by manganese alone in rats. Dosages varying from 1.88 to 15 mmol/kg MIBK were administered once, 18 hr prior to the administration of the cholestatic Mn-BR combination. The cholestatic effect of the manganese-bilirubin combination is enhanced with dosages of MIBK of 3.75 mmol/kg and more. Daily ketone pretreatment for 3 days resulted in an increased response to the cholestatic challenges of either Mn-BR or Mn alone. MIBK per se is devoid of cholestatic properties, since the bile flow measured prior to the cholestatic challenge is not decreased and in some cases is significantly greater than that from vehicle-pretreated animals. These results show that MIBK can potentiate cholestatic as well as necrogenic forms of hepatotoxicity.

Animals↗
PubMed1987

Chloroform interaction with chlordecone and mirex: correlation between biochemical and histological indices of toxicity and quantitative tissue levels.

The purpose of this study was to investigate whether the tissue distribution of chlordecone (CD) and mirex (M) might explain the difference in the potentiation of CHCl3 liver injury. Male Sprague-Dawley rats received either a single oral dose of CD or M (1, 2.5, 5, 10, 25, or 50 mg/kg) or three single daily doses of CD or M (0.5, 2, or 10 mg/kg). Eighteen hours following the last treatment, the animals were divided into two groups. The first group was killed and residues of CD or M in plasma, kidney, liver, and adipose tissue were measured by gas-liquid chromatography. The other group received CHCl3 (0.5 ml/kg, po) and was killed 24 hr later. Biochemical and histological indices of liver injury were evaluated. CD administered either singly or repetitively is more effective than M in potentiating the CHCl3-induced liver injury. This was exhibited by a higher increase in the plasma activities of the enzymes alanine aminotransferase and ornithine carbamoyl transferase and a greater alteration of the morphological pattern. There was a very good correlation between biochemical and histological indices. However, the severity of the liver injury did not parallel tissue concentrations. With M, a relatively poor potentiation of the liver damage was observed although adequate hepatic concentrations were present.

Adipose Tissue↗
PubMed1987

The role of biotransformation-detoxication in acetone-, 2-butanone-, and 2-hexanone-potentiated chloroform-induced hepatotoxicity.

The hepatotoxicity of chloroform (CHCl3) is thought to require biotransformation, by the polysubstrate monooxygenase system (P-450), to a reactive intermediate(s). Therefore, the potentiation of CHCl3-induced hepatotoxicity, which occurs following exposure to certain ketones, may hypothetically be explained by a reduced capacity of the cell to form glutathione conjugates (detoxicate the intermediate) and (or) by an increased rate of reactive intermediate(s) generation secondary to a modification of the P-450 system. To test these hypotheses, liver damage, as indicated by elevation in plasma alanine aminotransferase and ornithine carbamyl transferase activities, was modulated in male Sprague-Dawley rats by varying the time interval (10, 18, 24, 48, 72, 96 h) between acetone, 2-butanone, or 2-hexanone (15 mmol/kg, p.o.) pretreatment and CHCl3 (0.5 mL/kg, p.o.) administration. These data were compared with hepatic glutathione and with various parameters of the polysubstrate monooxygenase system: cytochrome P-450, cytochrome c reductase, cytochrome b5, and microsomal binding of 14CHCl3-derived radiolabel. Reduced detoxication capacity does not appear to be involved as hepatic glutathione levels were not reduced. Globally, a relationship between modifications to the polysubstrate monooxygenase system and potentiation of CHCl3-induced hepatotoxicity appears to exist. The rank order of each ketone's ability to modify P-450 parameters was the same in most instances as that based on peak ability to potentiate CHCl3-induced hepatotoxicity: 2-hexanone greater than 2-butanone greater than or equal to acetone. Therefore, these results suggest that a general relationship exists between the ketone-induced potentiation of CHCl3-induced hepatotoxicity and increased CHCl3 reactive metabolite generation. However, other factors may also contribute to the phenomenon.

Acetone↗
PubMed1987

Failure of phenobarbital or butanediol pretreatment to potentiate tienilic acid hepatotoxicity in vivo in the rat.

Tienilic acid, a uricosuric diuretic, has been associated with hepatocellular injury in humans as a low-incidence adverse reaction. This phenomenon suggests that a metabolic idiosyncrasy may be involved. In the present study, the effect of phenobarbital and 1,3-butanediol pretreatment, prior to tienilic acid challenge (50 or 100 mg/kg, i.v.) on rat hepatic function was studied in vivo. The following parameters were assessed: plasma alanine amino-transferase activity, plasma bilirubin concentration and bile flow. The results show that neither pretreatment would reveal that tienilic acid possesses hepatotoxic properties in the rat. The discrepancies between these results observed in vivo and those obtained by others in the isolated perfused rat liver suggest: a) that a metabolite formed (under normal conditions) via the phenobarbital- or butanediol-inducible forms of cytochrome P-450 is not a likely part of the hepatotoxic sequence of events; b) that the isolated perfused rat liver model in this case is not representative of the in vivo situation.

Alanine Transaminase↗
PubMed1986

Correlation between acetone-potentiated CCl4-induced liver injury and blood concentrations after inhalation or oral administration.

In studies of acetone-potentiated liver injury induced by haloalkanes, acetone is usually given by gavage, whereas industrial exposure to acetone normally occurs by inhalation. It was of interest to verify if the route of administration influences the potentiation. Male Sprague-Dawley rats were exposed for 4 hr to acetone vapors or treated orally with acetone; the minimal effective dose (MED) levels for potentiating CCl4-induced liver injury were estimated to be 2500 ppm and 0.25 ml/kg, respectively. Groups were treated with acetone using 0.4, 1, 2, 4, or 6 times the MED. Half of each group was killed at various time intervals after treatment for blood acetone measurements by gas chromatography; the other half was challenged with CCl4 (0.1 ml/kg, ip) 18 hr after acetone, and killed 24 hr later. Plasma alanine aminotransferase (ALT) activity and bilirubin concentrations were measured. Inhalation and oral administration of acetone both potentiated CCl4 toxicity. Rats exposed repetitively to acetone vapors (10 daily exposures) and subsequently challenged with CCl4 exhibited liver toxicity that was not significantly different from that of rats subjected to a single exposure. Correlations between ALT activities and maximal blood acetone concentrations were found to be linear (positive) and significant for both routes. For a given blood acetone concentration, however, toxicity was least severe following acetone exposure by inhalation. When the concept of threshold concentrations was applied to the data, the severity of the toxic response was dependent on the blood acetone concentration above the threshold, irrespective of the route of administration.

Acetone↗
PubMed1986

Modification of biliary tree permeability in rats treated with a manganese-bilirubin combination.

Previous studies in this laboratory demonstrated incorporation of manganese (Mn) and bilirubin (BR) in rat liver bile canalicular membrane (BCM) following a cholestatic regimen composed sequentially of Mn plus BR. The present study investigates biliary tree permeability using segmented retrograde intrabiliary injection (SRII) with [3H]mannitol and [3H]inulin as marker substances. Male Sprague-Dawley rats were given the following iv: (a) Mn (high and low dose), (b) BR, (c) sulfobromophthalein (BSP), (d) Mn-BSP-BR, (e) MnBR. Results obtained with mannitol showed a approximately 63% decrease (p less than 0.05) in marker recovery following administration of MnBR combination. While BSP alone had no effect on mannitol recovery, BSP abolished the MnBR response when administered in the Mn-BSP-BR sequence. With inulin, Mn (high dose), MnBR, and Mn-BSP-BR all produced a approximately 45% decrease (p less than 0.05) in recovery, while BSP or BR alone caused a approximately 25% decrease (p less than 0.05). Mn (low dose) was without effect. These results and others obtained when the time pattern of the MnBR treatment was modified suggest: (1) MnBR treatment increases biliary tree permeability by altering both BCM and the junctional complex; (2) BCM alteration is probably the more critical event, since BSP, which protects against MnBR cholestasis, protected against the MnBR-induced change in mannitol recovery, but exerted no effect on inulin recovery.

Animals↗
PubMed1986

Modifications in rat hepatobiliary function following treatment with acetone, 2-butanone, 2-hexanone, mirex, or chlordecone and subsequently exposed to chloroform.

Potentiation of haloalkane hepatonecrosis by various ketones is a well-documented observation. The present study investigates the hepatobiliary effects of such treatments. Male Sprague-Dawley rats were pretreated with acetone (A), 2-butanone (MEK), 2-hexanone (MBK), 15 mmol/kg (po), or chlordecone (CD) and its nonketonic analog, mirex (M), 50 mg/kg (po). Following the pretreatment at various time intervals ranging from 10 to 96 hr, groups of animals received a challenging dosage of CHCl3 (0.5 ml/kg, po). In a collateral experiment, groups of animals were pretreated with vehicle and 18 hr later received either 0.50, 0.75, or 1.00 ml/kg CHCl3 (po). In each case hepatobiliary function was evaluated 24 hr later using bile flow rate and plasma bilirubin concentration. The results showed (1) that the ketones alone had no effect; mirex alone increased bile flow; (2) CHCl3 alone had no effect on bile flow but slightly increased plasma bilirubin; (3) all pretreatments potentiated the effect of CHCl3 on plasma bilirubin; (4) combinations of A, MBK, or CD plus CHCl3 were cholestatic within a restricted time frame. A study of biliary tree permeability by the segmented retrograde intrabiliary injection technique, using mannitol and inulin as marker compounds, suggested that cholestasis may result from potentiation of CHCl3-induced alterations in canalicular membrane permeability.

Acetone↗
PubMed1986

Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity.

While the biotransformation of methyl n-butyl ketone (MnBK) in animals is well characterized, little is known about the quantitative relationship between hepatic and plasma MnBK concentrations. This study provides such information and emphasizes the usefulness of MnBK metabolite quantification, as well as MnBK-induced metabolic ketosis for the biological monitoring of MnBK exposure in rats. Elimination of MnBK was followed 24 hr after oral administration (0.95, 1.90, and 5.70 mmol/kg in corn oil) to male Sprague-Dawley rats. Two metabolites [2-hexanol (2HOL), and 2,5-hexanedione (2,5HD)] were also monitored and their kinetics determined. These data were compared to ketone body (KB) concentrations found in plasma and liver during the same period. Plasma concentrations of MnBK and 2,5HD correlated well with those in the liver. This was not the case for 2HOL. MnBK, 2HOL, and 2,5HD were no longer detected in plasma and liver 18 hr after dosing. Meanwhile, a marked ketosis was observed from 12 to 24 hr. This ketotic state was due to an increase in beta-hydroxybutyrate (BOHB), while acetoacetate remained at its basal levels. These data indicate that MnBK can induce ketosis in rats and suggest that the resulting BOHB might be used as an alternative biological monitor of MnBK exposures at high concentrations.

Administration, Oral↗