Biomedical subjects

G L Plaa

Publications and source records attributed to G L Plaa.

At least 37 records · Page 2Linked to original sources

PubMed1994

Metabolic fate of methyl n-butyl ketone, methyl isobutyl ketone and their metabolites in mice.

The metabolic fate of methyl n-butyl ketone (MnBK) and its isomer methyl isobutyl ketone (MiBK) was studied in mice. The concentrations of both ketones and their metabolites in blood and brain were measured at different time intervals after their administration. The principal metabolites of MnBK were 2-hexanol (2-HOL) and 2,5-hexanedione (2,5-HD), while those of MiBK were 4-methyl-2-pentanol (4-MPOL) and 4-hydroxy-4 methyl-2-pentanone (HMP). The administration of 2-hexanol by itself led to the appearance of both MnBK and 2,5-hexanedione which, when administered by itself, did not lead to the appearance of either MnBK or 2-hexanol. The administration of 4-methyl-2-pentanol resulted in the appearance of MiBK and HMP. The administration of HMP did not result in the appearance of MiBK or 4-MPOL. These results indicate that the metabolic fate of MnBK and MiBK is similar to that reported in other species.

Animals↗

PubMed1993

Plasma concentrations in methyl isobutyl ketone-potentiated experimental cholestasis after inhalation or oral administration.

In studies of methyl isobutyl ketone (MiBK)-potentiated cholestasis induced by taurolithocholic acid (TLC) or manganese-bilirubin (Mn-BR) combinations, MiBK is usually given by gavage whereas industrial exposure to MiBK normally occurs by inhalation. The present study was conducted to verify if the route of administration could influence the potentiation. Male Sprague-Dawley rats were treated with MiBK for 3 days orally or by inhalation (4 hr/day). The minimal effective doses (MED) for potentiating both models of intrahepatic induced cholestasis were estimated to be 3 mmol/kg or 400 ppm for the oral or inhalation route, respectively. Groups of rats were treated with 0.5, 1, or 2 times the MED. Half of each group was sacrificed after the last MiBK administration to determine plasma concentrations of MiBK and its metabolites by gas-liquid chromatography. The other half was challenged 18 hr later with TLC (30 mumol/kg) or a combination of manganese (4.5 mg/kg) and bilirubin (15 mg/kg). Bile flow was measured from 15 to 135 min after the cholestatic challenge. Rats exposed to MiBK orally or by inhalation exhibited an enhanced diminution in bile flow that was dose-dependent. With dosages of 3 mmol/kg po or 400 ppm by inhalation or more, diminution in bile flow was significantly different from control values. Comparisons between maximal bile flow decrease and MiBK plasma concentration showed that the severity of the hepatotoxic response was dependent on the plasma MiBK concentration, irrespective of the route of administration.

Administration, Inhalation↗

PubMed1992

Pathogenesis of lithocholate-induced intrahepatic cholestasis: role of glucuronidation and hydroxylation of lithocholate.

It has been shown that lithocholic glucuronide is more cholestatic than lithocholic acid (LCA), as well as its taurine and glycine conjugates. Furthermore, LCA hydroxylation is thought to be a major detoxifying mechanism. Therefore, the role of LCA glucuronidation and hydroxylation was investigated during the development of LCA-induced cholestasis and recovery from it. Male rats received a bolus intravenous injection of [14C]LCA (12 mumol/100 g body weight) and bile samples were collected every 30 min for 5 h. Bile flow (BF) was reduced immediately after LCA injection, dropping to 40% of basal BF at 60 min. It then started to increase, reaching normal bile flow values at 3.5 h. Morphologically, canalicular lesions were dominant at 60 min and virtually absent at 2 h. At 60 min (maximal cholestasis), 30% of the LCA injected was secreted in bile, 20% was found in plasma while the other 50% was recovered in the liver and distributed mainly in plasma membranes, microsomes and cytosol. At the end of the experiment (normal BF), 20% of the LCA injected was still in the liver but was present mainly in the cytosol. In bile, within 30 min after injection, 46% of the LCA secreted was lithocholic glucuronide, 24% was conjugated with taurine and glycine, and 21% was in the form of hydroxylated bile acids. During the recovery period, lithocholic glucuronide secretion decreased to 18-25%. Taurine and glycine conjugate secretion increased to a maximum of 43% at 60 min, after which it was reduced to 21-28%. In contrast, hydroxylated metabolites were elevated during the recovery periods, reaching a maximum (45%) at 120 min and remaining constant thereafter. These results suggest that: (i) LCA binding to plasma membranes and microsomes appeared to correlate with the development of cholestasis; (ii) LCA glucuronidation may initiate and/or contribute to LCA-induced cholestasis; and (iii) hydroxylation predominates during recovery from cholestasis.

Animals↗

PubMed1992

Potentiation of lithocholic-acid-induced cholestasis by methyl isobutyl ketone.

Methyl isobutyl ketone was found to potentiate intrahepatic cholestasis induced by taurolithocholate and the combination of manganese-bilirubin. The aim of this study was to elucidate the mechanism of this potentiation using the lithocholate-induced cholestasis model. Male rats were given methyl isobutyl ketone 7.5 mumol/kg body wt. daily for 3 days. The effect of this treatment on lithocholate-induced cholestasis, bile formation and taurocholic acid transport was examined. The data showed that methyl isobutyl ketone treatment potentiated lithocholate-induced cholestasis and reduced significantly bile salt, phospholipid and cholesterol secretion rates as well as the transport maximum of taurocholic acid. It is suggested that methyl isobutyl ketone potentiates lithocholate-induced cholestasis by reducing the bile salt pool and interfering with the haptic secretion rate of bile salts.

Animals↗

PubMed1992

Influence of agents affecting monooxygenase activity on taurolithocholic acid-induced cholestasis.

In rats, pretreatment with certain ketones results in enhanced taurolithocholic acid (TLCA)-induced reduction in bile flow, whereas pretreatment with inhibitors of protein synthesis diminishes the effect on bile flow of cholestatic regimens. In the present study, the possible role of cytochrome P-450 in the ketone potentiation phenomenon was investigated. Male rats were pretreated with inducers or inhibitors of hepatic cytochrome P-450 and the impact of these pretreatments on TLCA-induced cholestasis assessed. Phenobarbital, 3-methylcholanthrene, chlordecone or mirex were used as inducers, and SKF 525-A, piperonyl butoxide, or cobaltous chloride as inhibitors of monooxygenase activity. Phenobarbital and 3-methylcholanthrene pretreatment enhanced TLCA-induced reduction of bile flow, while mirex and chlordecone were without effect. The three inhibitors of monooxygenase activity did not diminish TLCA-induced cholestasis. Instead, piperonyl butoxide and cobaltous chloride appeared to enhance the action of TLCA. Consequently, an increase in cytochrome P-450 (or specific isozymes) as a common denominator in the potentiation phenomenon appears unlikely. While hepatic proteins may play an important role in the potentiation of TLCA-induced cholestasis following pretreatment with ketones, the pattern of potentiation after pretreatment of rats with different inducers or inhibitors of cytochrome P-450 does not appear to implicate this family of proteins.

Animals↗

PubMed1992

Modulation of hexachlorobenzene-induced hepatic porphyria by methyl isobutyl ketone in the rat.

Potential toxic interaction between hexachlorobenzene (HCB) and methyl isobutyl ketone (MiBK) was investigated using two different schedules of toxicant administration. The first schedule involved simultaneous administration of HCB (50 mg/kg/d, p.o. in 10 ml/kg corn oil at 10.00 a.m. for 5 d/wk) and MiBK (7.5 mmol/kg/d, p.o. in 10 ml/kg corn oil at 4.00 p.m. for 3 d/wk) for 6 weeks. The second schedule involved an initial dosing of 25 or 50 mg HCB/kg/d for 12 consecutive days, followed by the administration of 7.5 mmol MiBK/kg every other day for 27 days. When administered simultaneously, MiBK reduced the severity of HCB-induced porphyria, but when given sequentially after HCB accumulation, it enhanced the porphyrinogenic response. These results suggest that the effect of combined exposure to HCB and MiBK on hepatic porphyria depends on the sequence of the administration of both chemicals, and that the mechanism involved in this interaction may invoke both the induction and inhibition of specific hepatic isoenzymes by MiBK.

Administration, Oral↗

PubMed1992

Do intracellular Ca2+ activity and hepatic glutathione play a role in the pathogenesis of lithocholic acid-induced cholestasis?

The possible relevance of alterations in intracellular Ca2+ and hepatic glutathione levels (GSH) in the pathogenesis of cholestasis induced by lithocholic acid (LCA) was examined by comparing effects of LCA and acetaminophen on these parameters and bile flow (BF) in rats. Intracellular Ca2+ activity was measured via glycogen phosphorylase a determination in rats given an intravenous bolus injection of either LCA (12 mumol/100 g body wt.), acetaminophen (60 mg/100 g body wt.), or a mixed solution of LCA and acetaminophen. BF was reduced immediately after LCA administration, with a maximum decrease occurring at 60 min followed by an increase to normal values at 210 min. On the other hand, glycogen phosphorylase a activity was elevated during all time periods after LCA treatment. Hepatic glutathione followed the BF curves being markedly depleted at the peak of cholestasis (60 min) and normal in the total recovery period (210 min). In contrast, acetaminophen had no effect on BF but significantly increased glycogen phosphorylase a activity and depleted hepatic glutathione levels. These results suggest that cholestatic effect of LCA is not due to changes in intracellular Ca2+ or hepatic glutathione levels.

Acetaminophen↗

PubMed1992

Influence of various mixtures of inhaled toluene and xylene on the biological monitoring of exposure to these solvents in rats.

The present study was undertaken to describe the influence of simultaneous exposure by inhalation to toluene and xylene on some aspects of their respective metabolic disposition. Adult male rats were exposed acutely (5 h) to 75, 150, and 225 ppm of toluene or xylene and to various mixtures of these solvents: toluene (75 ppm) and xylene (225 ppm), toluene (150 ppm) and xylene (150 ppm), toluene (225 ppm) and xylene (75 ppm). Compared with single exposure, simultaneous exposure resulted in lower amounts of excreted hippuric acid (20-30%) and methylhippuric acids (4-40%) in urine over a period of 24 h, even though significant differences were seen only with the toluene (150 ppm) and xylene (150 ppm) combination. In addition, increased concentrations of solvents in blood (toluene, 230%; xylene, 500%) and in brain (toluene, 230%; xylene, 320%) were found during the immediate post-exposure period. Simultaneous exposure also enhanced the pulmonary elimination of both solvents (toluene, 190-240%; xylene, 340-650%). Influence of repeated simultaneous exposure (9 days) was investigated for the toluene (150 ppm) and xylene (150 ppm) combination and the results compared with those of repeated exposure to each solvent administered singly. Under these conditions, repeated simultaneous exposure decreased the excretion of urinary metabolites, but only after the first exposure. On the other hand, simultaneous exposure resulted in significantly higher concentrations of toluene (210%) and xylene (240%) in blood throughout the entire 9-day exposure period. These results strongly suggest mutual metabolic interactions (inhibition) between toluene and xylene that affect the metabolic disposition of both solvents and ultimately the biological monitoring of data of exposure to a combination of solvents in rats.

Administration, Inhalation↗

PubMed1991

Effect of simultaneous exposure to toluene and xylene on their respective biological exposure indices in humans.

Studies that specifically address the influence of controlled human exposure to a combination of solvents on the biological monitoring of exposure are limited in number. The present study was undertaken to investigate whether simultaneous exposure of human volunteers to toluene and xylene could modify the respective metabolic disposition of these solvents. Five adult Caucasian men were exposed for 7 consecutive h/day over 3 consecutive days to 50 ppm toluene and 40 ppm xylene either separately or in combination in a dynamic, controlled exposure chamber (low-level exposure). The experiment was repeated three times at intervals of 2 weeks. In another experiment, three subjects were exposed to 95 ppm toluene and 80 ppm xylene or a combination of both for 4 h (high-level exposure). The concentration of unchanged solvents in blood (B) and in end-exhaled air (EA) as well as the urinary excretion of hippuric acid (HA) and methylhippuric acids (MHAs) were determined. Simultaneous exposure to the lowest level of solvents did not alter the concentration of unchanged solvents in blood or in exhaled air (average of 3-weekly means; single vs mixed exposure at 6.5 h exposure): B-toluene, 77.1 vs 78.1 micrograms/100 ml; B-xylene, 67.6 vs 77.8 micrograms/100 ml; EA-toluene, 9.9 vs 9.5 ppm; EA-xylene, 5.3 vs 4.8 ppm. Similarly, mixed exposure did not modify the excretion of urinary metabolites during the 3- to 7-h exposure period: HA, 1.11 vs 1.11 g/g creatinine: MHAs, 0.9 vs 0.87 g/g creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Functional changes of the biliary tree associated with experimentally induced cholestasis: sulfobromophthalein on manganese-bilirubin combinations.

Administration of combinations of manganese (Mn) and bilirubin (BR) to rats results in a severe, but reversible diminution of bile flow, an effect that can be abolished if sulfobromophthalein (BSP) is given at a specific time prior to BR. Some studies suggest that changes in the bile canalicular membrane (BCM) are critical to the response. One aim of the present work was to determine if functional changes in BCM also become more marked with increasing doses of BR. A second aim was to investigate the protective effects of BSP on MnBR-altered biliary function. The permeability of the biliary tree was evaluated by the segmented retrograde intrabiliary injection (SRII) procedure in male Sprague-Dawley rats treated with varying combinations and dosages of Mn, BR, and BSP. [3H]Mannitol and [3H]inulin were used as marker substances of the biliary tree (canalicular membrane and tight junctions, respectively). Administration of Mn, followed 15 min later by BR, led to a reduction in bile flow that was dose-dependent on BR. The percentage recovery of both inulin and mannitol in bile after SRII also decreased significantly with increasing dosages of BR. When BSP was given 10 min before BR, MnBR-induced reduction in bile flow was abolished. BSP treatment also prevented MnBR-induced reduction in biliary recovery of both inulin and mannitol after SRII; this was more evident with mannitol than with inulin. BSP protection against MnBR cholestasis depends upon when it is administered relative to BR injection. The relationship of BSP relative to BR injection was comparable for both reduced bile flow and the recoveries of marker substances in bile after SRII. The data are consistent with the conclusion that changes in biliary tree permeability, particularly at the canalicular membrane, likely lead to MnBR-induced cholestasis.

Animals↗

PubMed1991

Inhalation versus oral administration of acetone: effect of the vehicle on the potentiation of CCl4-induced liver injury.

Acetone potentiation of liver injury is greater when corn oil is given with acetone 18 h prior to a challenge with CCl4. This study aimed to further characterize the effects of the vehicle used to administer acetone on the severity of acetone-potentiated CCl4-induced liver injury. The more severe acetone-potentiated liver injury observed when corn oil was the vehicle does not seem to be due to greater liver acetone concentrations. When corn oil was used as the vehicle to administer acetone, liver and blood CCl4 concentrations were not significantly different from those where water was the vehicle. Therefore the relationship between blood or liver acetone concentration and plasma ALT activity for orally-administered acetone was modified by corn oil. Liver triglyceride concentration measured 18 h after a gavage of corn oil was significantly higher than that for the water-treated group. A direct effect of corn oil on liver, in particular a promotion of the propagation phase in the lipid peroxidation process induced by CCl4, is proposed to explain the increase in acetone-potentiated CCl4-induced liver injury.

Acetone↗

PubMed1991

Influence of acetone on the severity of the liver injury induced by haloalkane mixtures.

Acetone potentiation of haloalkane-induced liver injury is a well-known phenomenon. Acetone-treated rats challenged with a trichloroethylene-CCl4 mixture exhibit a more sever liver injury than that predicted by the addition of the single potentiating effects of each. The purpose of the present study was to determine if acetone exerted similar interactions with other haloalkane mixtures. The testing protocol used was designed and performed to allow categorization of interactions occurring among two or three agents. Rats were treated (p.o.) with corn oil or acetone (10.2 mmol/kg) and were administered (i.p.) 18 h later 1,1-dichloroethylene (0.6 mmol/kg), trichloroethylene (5.6 mmol/kg), tetrachloroethylene (19.6 mmol/kg), 1,1,1-trichloroethane (10.0 mmol/kg), 1,1,2-trichloroethane (1.1 mmol/kg), 1,1,2,2-tetrachloroethane (1.0 mmol/kg), CHCl3 (6.2 mmol/kg), CCl4 (1.0 mmol/kg), or a mixture of two haloalkanes (all 28 combinations were tested). Liver injury was assessed 24 h later using plasma alanine aminotransferase activity and a quantitative histological evaluation. In corn oil pretreated rats, the hepatotoxic responses observed for the 28 mixtures were additive for 26 of 28 mixtures and supra-additive for 2 of 28, whereas in acetone-pretreated rats the responses observed were additive for 17 of 28, infra-additive for 10 of 28, and supra-additive for 1 of 28. Mixtures containing 1,1,1-trichloroethane or tetrachloroethylene resulted only in no change in toxicity or infra-additivity. Increased toxic responses (additivity and supra-additivity) were observed with certain binary mixtures containing CCl4, CHCl3, 1,1,2-trichloroethane, or 1,1-dichloroethylene.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗

PubMed1990

The influence of severity of bile flow reduction, cycloheximide, and methyl isobutyl ketone pretreatment on the kinetics of taurolithocholic acid disposition in the rat.

Pretreatment of rats with methyl isobutyl ketone (MIBK) potentiates the effect of taurolithocholic acid (TLCA) on bile flow, while cycloheximide pretreatment diminishes the cholestatic response. Experiments were performed to determine if the effects of the pretreatments were related to changes in the kinetic disposition of TLCA. Groups of rats were pretreated daily with either 7.5 mmol MIBK/kg po for 3 days or 3.55 mumol cycloheximide/kg ip for 2 days prior to an iv challenge of TLCA. Bile and blood samples were collected for 3 hr and the blood concentrations and biliary excretion of TLCA monitored. The severity of the bile flow reduction had a marked effect on the kinetic pattern of TLCA. The volume of distribution and bile disposition constant of TLCA decreased inversely with the severity of bile flow reduction, while the blood disposition constant increased. The total clearance of TLCA was not affected, but increasing the severity of the cholestasis altered the contribution of biliary and extrabiliary clearance to total clearance. The changes in the kinetics of TLCA observed in MIBK- and cycloheximide-pretreated rats were consistent with the effects the pretreatments exerted on TLCA-induced reduction in bile flow. They were interpreted to be the result of the effects of the pretreatments rather than their cause. Thus, pretreatment with MIBK and cycloheximide appears to exert a modulating effect on TLCA-induced cholestasis by mechanisms unrelated to an alteration of TLCA kinetic profile.

Animals↗

PubMed1990

Evidence for the involvement of organelles in the mechanism of ketone-potentiated chloroform-induced hepatotoxicity.

Ketones can potentiate the hepatotoxicity of haloalkanes in animals. This may be due, in part, to changes in organelle susceptibility. Male Sprague-Dawley rats were administered 15 mmol/kg (po) acetone, 2-butanone, 2-hexanone or 50 mg/kg (po) chlordecone or mirex (a nonketonic analog of chlordecone). Eighteen hours later, tests of organelle structure/function were performed (osmotic stress, respiration, and calcium pump activity). Other rats were given 14CHCl3 (0.5 or 1.0 ml/kg, po) 18 h after chlordecone or mirex administration. Three hours later, the organelle distribution of 14C was evaluated. In a final experiment, ketone-pretreated (chlordecone or 2-hexanone) animals were killed 6 h after CHCl3 administration and evaluated morphologically for evidence of modified organelle response. Acetone and chlordecone, when given alone, enhanced lysosomal fragility to osmotic stress; no changes in functional capacity of mitochondria or microsomes were observed. CHCl3-derived 14C in the mitochondrial fraction increased 2-fold in chlordecone-treated rats. Morphological evaluation suggested mitochondria respond differently to CHCl3 in ketone-pretreated (chlordecone or 2-hexanone) animals compared to corn oil-pretreated controls. These results support the concept that modifications of organelles contribute to the mechanism of ketone-potentiation of CHCl3-induced hepatotoxicity.

Animals↗

PubMed1990

The role of acinar zone 3 hepatocytes in bile formation: influence of bromobenzene treatment on bile formation in the rat.

The role of zone 3 hepatocytes in bile formation was determined when they were selectively destroyed by 3.8 mmol/kg b.w. of bromobenzene injected i.p. for 48 h, as compared to appropriate controls. Bromobenzene treatment resulted in 29 +/- 4.4% hepatic lobule necrosis localized in the zone 3 hepatocytes. Although bile flow and bile salt-independent flow were not affected, this treatment was associated with a significant reduction in bile salt, and phospholipid secretion. The bile salt pool and bile salt synthesis were also significantly decreased. These results suggest that necrosis of zone 3 hepatocytes induced by bromobenzene reduced bile acid synthesis which decreased bile salt pool and affected bile salt and phospholipid secretion rates. However, necrosis of zone 3 hepatocytes did not affect bile flow or the bile salt-independent flow, suggesting that hepatocytes of zones 1 and 2 maintained the normal bile salt-independent flow when zone 3 hepatocytes were damaged.

Animals↗

PubMed1990

Cholic acid and chenodeoxycholic acid transport in the hepatic acinus in rats. Effect of necrosis of zone 3 induced by bromobenzene.

The transport of cholic acid (CA) and chenodeoxycholic acid (CDC) and their influence on bile formation was investigated in rats treated with bromobenzene (BZ), a toxicant which selectively destroys zone 3 of the hepatic acinus. The necrosis equals 27-31% of the acinus cells. The absence of zone 3 in rats reduced the secretory rate maximum of CA and CDC by 18% (NS) and 25% (p less than 0.05), respectively. The maximum bile flow was not different from control during CA infusion but was lower during CDC infusion in BZ-treated animals. Although the bile acid concentration was lower in BZ-treated rats, only values obtained during the basal period and the beginning of the infusion reached the level of statistically significant difference. The bile salt-independent flow (BSIF) was not affected by the absence of zone 3. Our data suggest that zones 1 and 2 of the hepatic acinus can compensate for the secretion of CA and elaboration of BSIF when zone 3 is destroyed. However, necrosis of zone 3 reduces CDC secretion. Thus, the capacity for bile acid transport of the hepatocytes of different zones in the hepatic acinus may differ according to the circulating bile acid.

Animals↗

PubMed1990

Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites.

The hepatonecrogenic properties of chloroform (CHCl3) can be modified by the administration of various chemicals. The ability of methyl isobutyl ketone (MIBK) and its two major metabolites, 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK) to potentiate the liver injury induced by CHCl3 was assessed in rats. The parent compound and both metabolites significantly increased the liver damage induced by CHCl3, as demonstrated by the elevation of the plasma activity of two transferases alanine aminotransferase and ornithine carbamoyl transferase and by the severity of the morphological changes. Moreover, the minimally effective dosage needed to potentiate CHCl3-induced hepatotoxicity was approximately 5 mmol/kg for the three compounds. We also studied the inducing properties of MIBK (cytochrome P-450 liver content and the activity of aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and aminopyrine N-demethylase). Cytochrome P-450 content and the oxidation of aniline and 7-ethoxycoumarin were significantly increased with either a single (7.5 mmol/kg or greater) or a multiple (5.0 and 7.5 mmol.kg-1.day-1 for 5 days) administration of MIBK. An increase in the activity of the aminopyrine demethylase was also elicited by the repetitive administration of MIBK. With gel electrophoresis, we found that MIBK significantly increased the 52.1- and 54.1-kDa proteins, corresponding most probably to P-450 isozymes.

Animals↗

PubMed1990

Animal models.

A review of the major categories of animal test procedures used in the toxicological assessment of drugs is presented. Problems that persist include low incidence responses, the need for innovation in toxicological methods and current societal attitudes about drugs and chemicals. A better understanding of the biological phenomena involved in toxicological responses is needed to properly interpret animal data and eventually extrapolate these findings to humans.

Animals↗