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Biomedical subjects

G L Plaa

Publications and source records attributed to G L Plaa.

At least 73 records · Page 4Linked to original sources
PubMed1986

Acetone potentiation of rat liver injury induced by trichloroethylene-carbon tetrachloride mixtures.

Acetone potentiation of haloalkane-induced hepatotoxicity is well recognized. Others reported that trichloroethylene (TCE) can potentiate the hepatotoxicity induced by CCl4. The purpose of the present study was to determine if acetone (A) can potentiate the hepatotoxicity of haloalkane (HA) mixtures. We derived dose-response curves for the potentiation of TCE, CCl4, and TCE-CCl4 induced hepatotoxicity by acetone. Male Sprague-Dawley rats received acetone (0.25-1.5 ml/kg, po); 18 hr later, they received an ip injection of either TCE, 0.25 ml/kg; CCl4, 0.1 or 0.6 ml/kg; or a mixture of TCE and CCl4. Rats were killed 24 hr later, the livers excised, and plasma ALT activities and bilirubin concentrations determined. Histological evaluations were also performed. Neither A, TCE, or both in combination modified the biochemical indices. Acetone potentiation of CCl4-induced liver injury was greater than TCE-potentiation of CCl4. Acetone enhanced the hepatotoxic response of the TCE-CCl4 mixture. Thus, CCl4-induced hepatotoxicity was enhanced by the simultaneous administration of TCE, and this response was potentiated by the previous administration of acetone.

Acetone↗
PubMed1986

1,3-Butanediol-induced increases in ketone bodies and potentiation of CCl4 hepatotoxicity.

Evidence previously reported suggest that 1,3-butanediol (BD) enhances the hepatotoxic effect of a single small dose of carbon tetrachloride (CCl4) in a dose-related manner. The present study provides additional information concerning the quantitative relationship between the severity of the ketotic state produced by BD and the magnitude of the potentiation observed and emphasizes the use of ketone bodies (KB) to predict the potential hazard of the BD-CCl4 interaction. Liver damage was modulated in male Sprague-Dawley rats by varying the concentration of the BD solutions ingested prior to a CCl4 challenge (0.1 ml/kg, i.p.). These data were compared to ketone bodies in plasma, hepatic tissue and urine. BD produced a dose-dependent metabolic ketosis observable at dosages between 1.1 and 9.9 g/kg per day given for 7 days. Plasma and liver data correlated well together. Concomitantly, potentiation of the CCl4-induced liver injury was also dose-related for the same dosage range; the minimum effective dosage of BD for potentiation was estimated as 1.1 g/kg per day. The linear correlations between hepatic or plasma KB values and the indices of hepatic dysfunction (ALT, OCT) were highly significant. Using a semiquantitative method, a correlation was also found for the urinary KB data. These results suggest that plasma KB concentrations might be useful for predicting possible potentiation of the hepatonecrotic effect of CCl4 by BD.

Acidosis↗
PubMed1986

Temporal relationships between biotransformation, detoxication, and chlordecone potentiation of chloroform-induced hepatotoxicity.

Exposure to chlordecone (CD, Kepone) is known to increase the hepatotoxicity of chloroform (CHCl3) in rats. A time-course analysis was conducted relating several indices of biotransformation capacity with the ability of CD to potentiate CHCl3-induced hepatotoxicity. Male Sprague-Dawley rats were given a single administration of corn oil alone or CD (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8, 16, 20, 24, or 32 days posttreatment, groups of rats were killed and their livers were analyzed for (i) cytochrome P-450, NADPH-dependent cytochrome c reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible binding of 14CHCl3-derived radiolabel to microsomal protein. Similarly treated rats were challenged (2-32 days posttreatment) with CHCl3 (0.5 mL/kg po); 24 h later, liver damage was assessed by plasma alanine aminotransferase (ALT), plasma ornithine carbamyl transferase (OCT), plasma bilirubin, and hepatic glucose-6-phosphatase. CD potentiation was maximal 2 days posttreatment; and enhanced susceptibility to CHCl3 persisted up to 20-24 days post-CD treatment. In a parallel study animals treated with chlordecone were killed 8, 16, 20, 24, or 32 days later. Blood, kidney, liver, and adipose tissue samples were taken and analyzed for chlordecone content. The results suggest that a general temporal correlation exists between biotransformation rate (microsomal 14C binding), chlordecone content, and the severity of liver injury; the other parameters monitored do not appear to relate directly to the potentiation.

Alanine Transaminase↗
PubMed1985

Hepatic subcellular distribution of manganese in manganese and manganese-bilirubin induced cholestasis.

Administration of non-cholestatic doses of manganese (Mn2+) followed by injection of bilirubin (BR) results in a severe reduction in rat bile flow. Male Sprague-Dawley rats were given various doses of Mn2+ (2, 4.5, 8, and 18 mg/kg, i.v.) and killed 0.25, 1, 3, or 5 hr later. 54Mn2+ was used to evaluate Mn2+ content (micrograms/g protein) in different liver fractions: homogenate, mitochondria, microsomes, cytoplasm, nuclei-membrane fraction and liver cell plasma membrane fractions, one containing bile canalicular complexes (LCPM-BCM), the other containing sinusoidal membranes (LCPM-PM). In LCPM-BCM and LCPM-PM, two time-related patterns of Mn2+ content were observed. With non-cholestatic doses (2, 4.5, and 8 mg/kg), Mn2+ content decreased with time and rarely exceeded 50 micrograms/g protein. With 18 mg/kg (a cholestatic dose), Mn2+ content increased with time and reached values over 100 micrograms/g protein (3-5 hr), reflecting possible modification in membrane structure. BR caused a marked increase in Mn2+ content (at a dose of 4.5 mg Mn2+/kg) in LCPM-BCM (240%), approaching values seen with 18 mg Mn2+/kg, whereas in LCPM-PM it was less striking (50%). These and other results obtained with various treatments (cholestatic and non-cholestatic) suggest than Mn2+ concentration in bile canalicular membranes is a critical factor in both forms of cholestasis, and that BR can facilitate Mn2+ incorporation in the bile canalicular membrane.

Animals↗
PubMed1985

Taurolithocholate-induced intrahepatic cholestasis: potentiation by methyl isobutyl ketone and methyl n-butyl ketone in rats.

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK) and methyl n-butyl ketone (MBK). We investigated the possibility that these ketones could potentiate the cholestasis induced by taurolithocholate (TLC) in rats. Daily ketone pretreatment for 3 or 7 days resulted in an enhancement of the diminution in bile flow observed after TLC challenge. When the ketones were administered without TLC challenge, cholestasis was not observed; in fact, slight increases in bile flow did occur. The data suggest that MIBK may be more effective than MBK as a potentiator. Preliminary experiments with 2,5-hexanedione (HD), a metabolite of MBK and a potent potentiator of haloalkane hepatonecrosis, were included in the study. HD appeared to be a less potent potentiator of TLC-induced cholestasis. Although some ketones can potentiate cholestatic as well as hepatonecrogenic reactions, different mechanisms of action appear to be involved in these two phenomena.

Animals↗
PubMed1985

Results of a 90-day toxicity study on 1,2,3- and 1,1,2-trichloropropane administered via the drinking water.

Trichloropropanes have been identified as environmental contaminants in sediments of the Great Lakes region of North America. Since these chemicals had the potential to find their way into drinking water, a 90-day feeding study was carried out in order to determine their subchronic toxicity. Groups of 10 male and 10 female weanling Sprague-Dawley rats were supplied drinking water ad libitum, containing 1,2,3- or 1,1,2-trichloropropane at concentrations of 1, 10, 100 or 1000 mg/L for 13 weeks. Emulphor (0.5%) was used to solubilize the chemicals. At the end of the study, the animals were killed and examined for gross and microscopic changes. Heart, liver, brain, kidney and spleen were excised and weighed. Blood was collected and subjected to a comprehensive hematological analysis. Serum was collected and profiled for changes in 12 biochemical parameters and a portion of liver was used to determined mixed function oxidase activity. Although three animals died during the study, their deaths could not be related to treatment. Decreased growth rate was observed in both sexes of the group receiving 1000 mg/L 1,2,3-trichloropropane. There was an increase in liver, kidney and brain weights (relative to body weight) in rats of both sexes fed 1000 mg/L 1,2,3-trichloropropane. Fatty livers were observed in some of the treated animals but a clear dose-relationship was not evident. An elevation in serum cholesterol was observed in female rats fed the highest dose of 1,2,3-trichloropropane.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Temporal analysis of rat liver injury following potentiation of carbon tetrachloride hepatotoxicity with ketonic or ketogenic compounds.

The administration of some ketonic or ketogenic compounds prior to a challenging dose of CCl4 potentiates the hepatic damage induced by this haloalkane. However, nothing is known about the recovery from the liver injury in these cases of chemically induced potentiation. To investigate this problem, we performed a temporal analysis of the hepatotoxic response of male Sprague-Dawley rats to CCl4 following a single pretreatment (p.o.) with: n-hexane, 2-hexanone, 2,5-hexanedione (15 mmol/kg in corn oil), isopropanol, acetone (33 and 34 mmol/kg in water, respectively); or the vehicle alone (10 ml/kg). They received, 18 h later, an i.p. injection of CCl4 (0.1, 0.75 or 1.0 ml/kg) and were killed 24-120 h later. Liver damage was assessed biochemically (ALT, OCT) and morphologically. A good correlation between biochemical and morphological results was observed. The ketonic or ketogenic compounds studied potentiated the liver injury produced by 0.1 ml/kg CCl4. Relative ranking orders regarding severity of maximal hepatic damage induced and time needed for complete recovery of liver injury were established; time of recovery was dependent on the maximal severity of the lesion, regardless of the potentiation. The results show that the temporal evolution of CCl4-induced liver injury is not markedly influenced by the administration of ketonic or ketogenic compounds as pretreatments, but rather depends on the severity of the maximal damage induced by the overall treatment.

Administration, Oral↗
PubMed1983

The effect of ethanol on the absorption, accumulation and biotransformation of xenobiotics by the isolated perfused rabbit lung.

The effects of acutely administered ethanol on absorption, accumulation and biotransformation of several model compounds were examined in the isolated perfused lung (IPL). To determine pulmonary accumulation imipramine and paraquat were studied. To determine the effect of ethanol on the absorption of substances from the airways into the blood sulfanilic acid was used as an example of a relatively lipid soluble compound while mannitol was chosen as a non-lipid soluble compound. Aldrin was chosen to demonstrate the effects of circulating ethanol on pulmonary biotransformation. The results obtained with imipramine and paraquat indicate that after a 60-min perfusion period 93% and 20% of the original amount added are respectively lost from the blood perfusate. Ethanol at an initial concentration of 300 mg/100 ml has no apparent effect either on the rate or the quantities accumulated by the lungs. When sulfanilic or mannitol were administered into the airways both compounds appeared in the perfusate and ethanol had no effect on this absorption. Finally we obtained evidence that aldrin is converted to dieldrin by the IPL but that the quantities metabolized are not modified by the presence of ethanol.

Absorption↗
PubMed1983

Dose-dependent modification of 1,1-dichloroethylene toxicity by acetone.

The ability of acetone to potentiate the toxicity of 1,1-dichloroethylene (DCE) in male rats was investigated. A biphasic potentiation of DCE-induced hepatotoxicity was observed; low doses (5 and 10 mmol/kg, p.o.) of acetone were active, whereas higher doses (15 and 30 mmol/kg) were not. Nephrotoxicity was not affected.

Acetone↗
PubMed1983

Acetone-induced potentiation of trihalomethane toxicity in male rats.

The acute hepato- and nephrotoxic potentials of two trihalomethane water contaminants, bromodichloromethane (BrCHCl2) and dibromochloromethane (Br2CHCl), were determined in male Sprague-Dawley rats. Br2CHCl possessed a greater hepatotoxic and lethal potential than BrCHCl2. However, both Br2CHCl and BrCHCl2 were weak hepatotoxicants as compared to a related trihalomethane, CHCl3. Br2CHCl and BrCHCl2 did not produce liver injury until near-lethal dosages were administered. Neither trihalomethane appeared to produce appreciable kidney injury during the 24-h challenge period. Pretreatment of rats with acetone (15 mmol/kg, p.o.) markedly potentiated the hepatotoxic response to BrCHCl2 and Br2CHCl. The potentiated response observed with acetone plus BrCHCl2 or Br2CHCl was equal to or greater than that observed with acetone plus an approximately equimolar dosage of CHCl3. That is, acetone appeared to convert these weak hepatotoxicants into strong hepatotoxicants.

Acetone↗
PubMed1983

Relationship between the carbon skeleton length of ketonic solvents and potentiation of chloroform-induced hepatotoxicity in rats.

Previous studies have suggested that ketonic solvents potentiate the hepatotoxic action of CHCl3 in rats. In addition, the relative potentiating capacity of the ketones appeared to be related to the length of their carbon skeleton. To test this hypothesis CHCl3-induced liver injury was evaluated in male Sprague-Dawley rats pretreated (15 mmol/kg, p.o.) with acetone (Ac), 2-butanone (Bu), 2-pentanone (Pn), 2-hexanone (Hx) or 2-heptanone (Hp). After 18 h, a challenging dose of CHCl3, (0.50 or 0.75 ml/kg, i.p.) was given. Liver damage was evaluated 24 h after CHCl3 administration by determining elevations in plasma GPT and OCT activity. Neither Ac, Bu, Pn, Hx, Hp or the CHCl3 challenging dosages produced marked liver injury when given alone. However, each of the ketones potentiated CHCl3-induced liver damage. The severity of the potentiated hepatotoxic response was significantly (positively) correlated with the ketone carbon chain length. These observations suggest that carbon skeleton length may play a role in determining the relative potentiating capacity of ketonic solvents.

Alanine Transaminase↗
PubMed1983

Potentiation of thioacetamide-induced hepatotoxicity in alloxan- and streptozotocin-diabetic rats.

Thioacetamide-induced hepatoxicity was potentiated in male Sprague-Dawley rats rendered diabetic by alloxan or streptozotocin. The response was more striking in alloxan-diabetic rats. Insulin administration prevented the potentiation following alloxan pretreatment. Fasting also resulted in an enhanced hepatotoxic response to thioacetamide, but the increase was much less than that observed in rats given the diabetogenic agents. The ketosis produced by alloxan was more severe than that induced by streptozotocin, but was unlike that caused by fasting. Pretreatment with phenobarbital, 3-methylcholanthrene or 3,4-benzpyrene did not enhance thioacetamide liver injury.

Acetamides↗
PubMed1983

A semiquantitative morphologic assessment of chlordecone-potentiated chloroform hepatotoxicity.

A semiquantitative morphologic procedure has been applied to chlordecone potentiation of CHCl3-induced liver injury in male Sprague-Dawley rats. The distance of the injured area from the terminal hepatic venule (THV) to the portal area was measured and the damaged cells were classified by type. The results were plotted graphically, along with elevations in plasma enzyme activities (GPT and OCT), to depict the pattern of damage. Chlordecone pretreatment enhanced the severity of the CHCl3-induced cellular changes and increased the number of cells affected. Dosages of 5 mg/kg of chlordecone did not potentiate CHCl3 toxicity, but higher dosages (10-50 mg/kg) enhanced the toxic response in a dose-dependent manner.

Alanine Transaminase↗
PubMed1982

The effect of alpha-naphthylisothiocyanate on bile secretion prior to and during the onset of cholestasis in the rat.

The effect of alpha-naphthylisothiocyanate (ANIT) on bile flow, erythritol clearance, bile acid excretion and bilirubin excretion was studied in rats. The median time-to-effect (Et50) for the appearance of cholestasis was about 15 h. ANIT failed to exert a gradual effect on bile flow or erythritol clearance before the onset of cholestasis. However, 3 h before complete cessation of bile flow, a rapid decline in bile flow and bile acid excretion was observed. Bile acid-independent flow was markedly reduced. However, the bile acid-dependent component was also affected.

1-Naphthylisothiocyanate↗
PubMed1982

Isopropanol and acetone potentiation of carbon tetrachloride-induced hepatotoxicity: single versus repetitive pretreatments in rats.

Acute oral pretreatment of rats with isopropanol or acetone results in a dose-related potentiation of CCl4 hepatotoxicity. Minimally effective doses (MED) and noneffective doses (NED) of both agents were estimated to be 0.25 and 0.10 ml/kg, respectively. Six MED given twice a day over 3 d caused a greater potentiation than a single MED, but not as much as that produced by the total dose given singly. Six NED given over 3 d did not potentiate CCl4, whereas the total dose did when given singly. A threshold for isopropanol and acetone appears to exist in the rat. A total dose of 1.5 ml/kg acetone was administered by four different treatment regimens (bolus, divided doses, infusion) over 3 d. Potentiation of CCl4 hepatotoxicity was then correlated with blood pharmacokinetic parameters: area under the concentration-time curve and peak blood concentration. An excellent correlation was found between the degree of potentiation observed and the peak blood concentration attained, but no correlation was found with area under the curve. Results of iv acetone infusions (over 3 d) with higher doses support the hypothesis that a threshold concentration of acetone is critical in the potentiation of CCl4 hepatotoxicity in the rat.

1-Propanol↗