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At least 19 recordsLinked to original sources
PubMed1978

The effect of 2-hexanone and 2-hexanone metabolites on pupillomotor activity and growth.

Neurotoxic agents such as MBK (2-hexanone) and MBK metabolites were fed in drinking water to guinea pigs. Effects of these solvents on locomotor activity were studied. Dynamic pupillometry indicated that MBK, 2,5-hexanedione and 2-hexanol decreased pupillary response throughout the first five weeks; by the 24th week, all treatment groups showed a greatly impaired pupillary response. From biotransformation studies, it is possible that the 2-hexanol effect on pupillary response may be attributed to its conversion to MBK and/or 2,5-hexanedione. Each of the solvents increased body weight, but decreased locomotor activity. The pupillary changes reported here may serve as an index of solvent exposure in the work environment, if such measurements were to be conducted on workers.

Animals↗
PubMed1987

The relevance of 4,5-dihydroxy-2-hexanone in the excretion kinetics of n-hexane metabolites in rat and man.

Male Wistar rats were exposed to n-hexane concentrations between 50 and 3000 ppm for 8 h, and urinary excretion kinetics of the n-hexane metabolites 1-hexanol, 2-hexanol, 3-hexanol, 2-hexanone, 2,5-hexanedione, and 4,5-dihydroxy-2-hexanone were assessed. The amounts of metabolites excreted were linearly dependent on the n-hexane exposure concentration, up to an exposure of about 300 ppm. Above 300 ppm exposure the metabolite excretion indicated saturation kinetics in the metabolism of n-hexane. In its quantity, the newly described 4,5-dihydroxy-2-hexanone was the second metabolite, its amount in the urine being about ten times higher than that of excreted 2,5-hexanedione. Using gas chromatography-mass spectrometry the occurrence of 4,5-dihydroxy-2-hexanone as an n-hexane metabolite in urine of man was confirmed after exposure of a male volunteer to a mean of 217 ppm n-hexane for 4 h (laboratory exposure). Twenty-six hours after starting this exposure the excretion of 4,5-dihydroxy-2-hexanone (as a result of the n-hexane exposure) reached a level which was four times higher than the excretion of 2,5-hexanedione. The results in both rat and man indicate the relevance of 4,5-dihydroxy-2-hexanone as a metabolite of n-hexane metabolism. Formation of this metabolite may be viewed as a route of detoxification.

Adult↗
PubMed1985

Analysis of n-hexane, 2-hexanone, 2,5-hexanedione, and related chemicals by capillary gas chromatography and high-performance liquid chromatography.

Analytical methods, using capillary gas chromatography and normal-phase high-performance liquid chromatography, were developed for the analysis of the neurotoxic chemicals n-hexane, 2-hexanone, and 2,5-hexanedione and their suspected metabolites. Two gas chromatographic methods, using a 50-m glass capillary OV 101 column and cyclohexane as an internal standard, were employed. In both methods, the injector and detector temperatures were 220 and 280 degrees C, respectively. In method I the following temperature program was used: isothermic at 50 degrees C for 30 min, followed by a temperature increase of 10 degrees C/min to a final temperature of 180 degrees C, which was then maintained for 7 min. This method was used to analyze the following compounds: n-hexane, 2,5-dimethylfuran, 2-hexanone, 3-hexanone, hexanal, 1-hexanol, 2-hexanol, 3-hexanol, 5-hydroxy-2-hexanone, gamma-valerolactone, 2,5-hexanedione, and 2,5-hexanediol. Method II, which was developed for n-hexane and eight of its more common metabolites, used the following temperature program: isothermic at 70 degrees C for 15 min, followed by a temperature increase of 40 degrees C/min to a final temperature of 220 degrees C, which was maintained for 5 min. A linear relationship between peak area and amount injected was observed over a 100-fold range. The minimum detectable amounts ranged from 0.05 to 1 microgram, depending on the compound. Normal-phase HPLC, using a 5-micron silica cartridge fitted into an RCM-100 radial-compression separation system, was utilized to analyze 2-hexanone and its metabolites 2,5-dimethylfuran, gamma-valerolactone, 5-hydroxy-2-hexanone, and 2,5-hexanedione.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, Gas↗
PubMed1991

Immunochemical detection of cytochrome P450 isozymes induced in rat liver by n-hexane, 2-hexanone and acetonyl acetone.

Cytochrome P450 isozymes induced in rat liver by treatment with n-hexane, 2-hexanone and acetonyl acetone (given intraperitoneally 5 mmol/kg for 4 days) were investigated using enzyme assays (benzene, toluene, 7-ethoxyresorufin and 7-pentoxyresorufin metabolism) and monoclonal antibodies (anti-P450IA1/2, anti-P450IIB1/2, anti-P450IIC11/6, anti-P450IIE1(91) and anti-P450IIE1(98)). n-Hexane treatment enhanced the activities of low-Km benzene aromatic hydroxylase and toluene side-chain oxidase, but not 7-ethoxyresorufin O-deethylase or 7-pentoxyresorufin O-depentylase. 2-Hexanone or acetonyl acetone treatment enhanced the activities of low- and high-Km benzene aromatic hydroxylases, toluene side-chain oxidase and 7-pentoxyresorufin O-depentylase, but not of 7-ethoxyresorufin O-deethylase. Immunoblot analysis showed that anti-P450IA1/2 did not bind liver microsomal protein from either control and treated rats in the region of cytochrome P450s, whereas with anti-P450IIE1(98) a clear-cut band was seen in liver microsomes from control and treated rats, with intensities in the following order: 2-hexanone = acetonyl acetone greater than or equal to n-hexane greater than control greater than phenobarbital. With anti-P450IIB1/2, a band was detected in microsomes from phenobarbital-treated rats, and to a lesser extent, in microsomes from 2-hexanone- and acetonyl acetone-treated rats. Like the immunoblot analysis, anti-P450IIE1(91) inhibited toluene side-chain hydroxylase activity in all microsomes, except in preparations from phenobarbital-treated rats and anti-P450IIB1 in microsomes from phenobarbital-, 2-hexanone- and acetonyl acetone-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

4,5-Dihydroxy-2-hexanone: a new metabolite of N-hexane and of 2,5-hexanedione in rat urine.

Male Wistar rats were exposed to 2000 ppm n-hexane or were treated with a single dose of 2,5-hexanedione (200 mg kg-1). Analysis of the urine collected after both treatments revealed the formation of 4,5-dihydroxy-2-hexanone via 5-hydroxy-2-hexanone or 2,5-hexanedione, respectively. Identification of this new n-hexane metabolite included enzymatic hydrolysis of the excreted glucuronide, derivatization of the keto group with O-methylhydroxylamine, and subsequent GC-MS analysis. The chemical structure derived from the mass spectra obtained was confirmed by further analysis of the methoxime-TMS derivatives and of deuterated 4,5-dihydroxy-2-hexanone excreted after treating rats with 2,5-[2H10]-hexanedione. 4,5-Dihydroxy-2-hexanone is proposed to be identical with a urinary constituent that is excreted by rats after n-hexane exposure and is converted to 2,5-dimethylfuran or 2,5-hexanedione, respectively, depending on the conditions of urine treatment prior to GC-MS analysis.

Acetates↗
PubMed1984

2-hexanone potentiation of [14C]chloroform hepatotoxicity: covalent interaction of a reactive intermediate with rat liver phospholipid.

Rats were treated with [14C]chloroform (14CHCl3) in corn oil (CO) or corn oil alone 18 hr following pretreatment with 2-hexanone (2-HX) in corn oil or corn oil alone. Livers were removed, homogenized 1,2, and 6 hr post-14CHCl3 administration, and glutathione (GSH) content, irreversible binding of 14CHCl3-derived radiolabel, and phospholipid composition were determined. The combination of 2-HX + CHCl3 reduced GSH content to 21% of control (CO + CO) 1 hr after CHCl3 administration. No significant rebound of GSH was observed 24 hr post-CHCl3 administration. In contrast, GSH was not altered by administration of CHCl3 to CO-pretreated rats. Although 14CHCl3-derived radiolabel was irreversibly bound to hepatic macromolecules of both CO- and 2-HX-pretreated rats, total irreversibly bound 14C was significantly enhanced in 2-HX-pretreated rats at all time points. The latter observation was consistent with the decrease in GSH of 2-HX-pretreated rats. Total 14C binding in 2-HX-pretreated rats reached a plateau 2 hr post-14CHCl3 administration and was distributed 52% in protein, 41% in lipid, and 7% in acid soluble fractions 6 hr post-14CHCl3 administration. 2-HX enhanced 14C binding to protein and lipid at each time point. Radiolabel was not detected in neutral lipids of control or 2-hexanone-treated animals, but was enhanced 33-fold in phospholipids of 2-hexanone-treated animals. Phospholipid fatty acid methyl ester derivatives did not contain 14C indicating the radiolabel was most likely associated with phospholipid polar head groups. Two dimensional thin layer chromatographic analysis of phospholipid from treated animals demonstrated that 87% of the total radiolabel was associated with a specific phospholipid (14C-PL) which had a 1:1 molar ratio of phosphate to 14C. The latter indicates that the 14C-PL was a monophospholipid derivative of 14CHCl3 reactive intermediate, generally thought to be phosgene. Concurrent decrease in phosphatidylethanolamine content from 23% of total phospholipid to 7%, accumulation of 14C-PL to 2.6% of total phospholipid, and increase in lysophosphatidylethanolamine from 1 to 7% of total phospholipid during 2-hexanone + 14CHCl3 treatment indicated that the amine moiety of phosphatidylethanolamine polar head groups was the probable target of phosgene-lipid interaction, and that a degradative pathway existed which removed the abnormal phospholipid from hepatic membranes. No phospholipid other than phosphatidylethanolamine was depleted. During models studies, 2% phosgene in toluene was reacted with liver phosphatidylethanolamine for 6 hr at 37 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1979

Simultaneous determination of n-hexane, 2-hexanone and 2,5-hexanedione in biological tissues by gas chromatography mass spectrometry.

A quantitative method is reported for the determination of n-hexane, 2-hexanone and 2,5-hexanedione in biological tissues by stable isotope dilution using gas chromatography mass spectrometry. n-[2H14]Hexane, 2-[2H5]hexanone and 2,5-[2H10]hexanedione are used as the isotopic diluents. After tissue homogenization and extraction of the three compounds in the presence of the deuterated internal standards, analysis is carried out in a single gas chromatographic injection by selected ion monitoring. Principal advantages of the technique are the ease of sample handling, rapidity of analysis and low limits of detection. The methodology is used to determine the organ distribution, pharmacokinetics and metabolism of n-hexane to 2-hexanone and 2,5-hexanedione in rats following inhalation exposure.

Animals↗
PubMed1984

An electrophysiological study of 2-hexanone and 2,5-hexanedione neurotoxicity in rats.

n-Hexane and its metabolites are neurotoxic to animals and man. Studies have revealed a progressive neuropathy which affects the distal regions of motor and sensory peripheral nerves. This paper describes efforts to determine whether 2-hexanone or 2,5-hexanedione is more neurotoxic than 2-hexanone and that it first affects the distal axon. Concentrations of 20 mM produced no effects after 3 weeks but 40 mM increased distal latency after 2 weeks.

Administration, Oral↗
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↗
PubMedDate not supplied

Synthesis and antimicrobial activity of 3-hydroxyimino-5-methyl-2-hexanone(HIMH) and its dioxime derivative.

A new oxime, 3-hydroxyimino-5-methyl-2-hexanone (HIMH) has been synthesized by the reaction of 1-pentyl nitrite with 5-methyl-2-hexanone under acidic conditions. The subsequent treatment of HIMH with NH2OH x HCl gives 5-methyl-2,3-hexanedione dioxime (H2MHDDO). The structures of these compounds have been confirmed by physicochemical and spectral data. A preliminary screening of these compounds for biological activity against several microorganisms has indicated that they are selective growth inhibitors of m-tuberculosis, in particular.

Anti-Bacterial Agents↗
PubMed1982

Toxicity and metabolism of the neurotoxic hexacarbons n-hexane, 2-hexanone, and 2,5-hexanedione.

Human exposure to hexacarbon compounds is quite pervasive, including occupational exposures to industrial solvents as well as unintentional and sometimes deliberate exposures to hexacarbon solvents contained in innumerable commercial products. The exact mechanism of hexacarbon neurotoxicity has not yet been identified, but an interference with neuronal axoplasmic flow seems most likely. Metabolism of n-hexane and 2-hexanone to 2,5-hexanedione is a prominent feature which appears to be causally related to the neuropathologic syndrome, and mixed solvent effects have been noted in regard to potentiation of hexacarbon neurotoxicity. Continued effort in investigating the chemically induced peripheral neuropathy is essential not only to define the precise molecular mechanism, but to advance our basic understanding of other polyneuropathies as well. Ultimately, progress in these areas should yield such benefits as early diagnosis of potential neuropathology, better measures for the prevention of neurotoxicities, and more effective modalities of treatment. Indeed, sustained research efforts are imperative in maintaining human health and safety throughout our current era of advancing global technology.

Animals↗
PubMedDate not supplied

Synthesis, structural characterization and antimicrobial studies of hydrazone derivatives of 3-hydroxyimino-5-methyl-2-hexanone.

The derivatives of 3-hydroxyimino-5-methyl-2-hexanone oxime have been obtained in good yield by its reactions either with hydrazine hydrate or phenyl hydrazine, respectively. IR and 1H NMR spectral data of these compounds have been discussed. All the newly synthesised compounds have been tested for their biological activity against S. auerus, S. typhi, C. albicans, A. niger, S. cerevisiae and M. tuberculosis H47RV.

Anti-Bacterial Agents↗
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↗
PubMed1984

Mechanisms in 2-hexanone potentiation of chloroform hepatotoxicity.

2-Hexanone (2-Hx) is known to potentiate chloroform (CHCl3) hepatotoxicity in part by increasing the bioactivation of CHCl3 to phosgene (COCl2). Treatment of rats with 2-Hx + CHCl3 in vivo did not initiate peroxidation of hepatic fatty acids as determined by formation of conjugated dienes or depletion of unsaturated fatty acids, or as determined by production of malondialdehyde (MDA) in vitro. A 5-fold decrease in the specific activity of succinate-dependent cytochrome c reductase in liver from rats treated in vivo with corn oil (vehicle) + CHCl3 and in rats treated with 2-Hx + CHCl3 indicated that a mechanism independent of CHCl3 bioactivation may add to the hepatotoxic effects which result from the metabolism of chloroform to phosgene.

Animals↗
PubMed1986

Renal and hepatic interactions between 2-hexanone and carbon tetrachloride in F-344 rats.

Fisher-344 rats were pretreated with 2-hexanone (HX) and challenged with carbon tetrachloride (CCl4) in a replicated 3 X 4 factorial experiment to determine if HX potentiated CCL4-induced renal and hepatic damage. Rats given both HX and CCl4 demonstrated more severe hepatic injury at 24 and 48 h than did controls. However, in contrast to our experience with chloroform (CHCl3), CCl4-induced renal injury in HX-pretreated rats was only slightly greater than in vehicle-pretreated controls.

Administration, Oral↗
PubMed1990

Gonadotoxic effects of 2-hexanone and 1,2-dibromo-3-chloropropane on the enzymatic activity of rat testicular 17 alpha-hydroxylase/C17,20-lyase.

In this study the gonadotoxic effects of 2-hexanone administered as a pretreatment and/or 1,2-dibromo-3-chloropropane administered as a challenge on the activity of several key steroidogenic enzymes in the rat testis were examined. Despite the absence of an effect when either treatment was administered individually, the pretreatment/challenge combination inhibited the steroidogenic capacity of the rat testis. The specific activity of testicular 17 alpha-hydroxylase was significantly reduced (P less than 0.05), with respect to the control, following the pretreatment/challenge combination. There were no significant differences between the control and the individual treatments. The inhibition of 17 alpha-hydroxylase activity occurred in the absence of significant differences in testis weight and testicular protein content. This inhibition of testicular steroidogenic enzyme activity was specific as the activity of another testicular enzyme, namely C17,20-lyase, was not affected by any treatment. The decline in rat testicular 17 alpha-hydroxylase activity 18 h after the 1,2-dibromo-3-chloropropane challenge precedes the reported alterations in the seminiferous epithelium following this same treatment. The results of the present study indicate that the steroidogenic cell of the testis, i.e. the Leydig cell, is a potential site for the primary toxic effects of these agents in the rat testis.

Animals↗