Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone*1, *2

Ralston, William; Hilderbrand, Richard L.; Uddin, David E.; Andersen, Melvin E.; Gardier, Robert W.

doi:10.1016/0041-008x(85)90169-3

Cited by 38 publications

(17 citation statements)

References 17 publications

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“…This phenomenon was also suggested recently by Ralston et al (9) for the potentiation of the neurotoxicity of 2,5-HD by methyl ethyl ketone. The effect on Cl bOdY was not very marked, but in rat experiments where acetone and 2,5-HD are given with drinking water for several weeks, a slight change in the body clearance of 2,5-HD may more greatly influence the steady-state plasma concentration of 2,5-HD.…”

Section: Resultsmentioning

confidence: 54%

“…The mechanism is not fully understood (9,II), but experimental data support the idea that the potentiation is partly due to the persistence of the neurotoxic metabolites in the blood or due to the formation of more of the metabolites of n-hexane, changes in the protein binding of 2,5-HD, or changes in the distribution of the metabolites (9,II) . In a previous report it has been shown that acetone, another ketone, may also potentiate the neurotoxicity of 2,5-HD in rats (6).…”

mentioning

confidence: 99%

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Acetone-induced changes in the toxicokinetics of 2,5-hexanedione in rabbits.

Ladefoged¹,

Perbellini²

1986

Scand J Work Environ Health

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Section: Resultsmentioning

confidence: 54%

mentioning

confidence: 99%

Acetone-induced changes in the toxicokinetics of 2,5-hexanedione in rabbits.

Ladefoged¹,

Perbellini²

1986

Scand J Work Environ Health

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“…Ralston et al (1985) found concomitant administration of MEK and 2,5-HD increased the (2-9 h) AUC of 2,5-HD from 456 to 811 lg h/ml in rats orally exposed once to 2,5-HD alone and 2,5-HD plus MEK, respectively. In an experiment using rats Table 2 for model parameters].…”

Section: Discussionmentioning

confidence: 96%

“…The symbols represent experimental data from Yasui et al (1995) repeatedly exposed for 7 days, the AUC increased from 549 to 860 lg h/ml in groups receiving 2,5-HD alone and 2,5-HD plus MEK, respectively. Ralston et al (1985) postulated that the increased persistence of 2,5-HD observed in rats was due to competitive inhibition of 2,5-HD by MEK. Yasui et al (1995) show similar results in rats injected subcutaneously with 2,5-HD and MEK at different doses.…”

Section: Discussionmentioning

confidence: 98%

“…The neurotoxic effect is characterized by La and Swenberg 1996;Perera 1996) Fig. 2 Major metabolic pathways of n-hexane and its metabolites (adapted from Krasavage et al 1980;Fedtke and Bolt 1987;Manini et al 1998) is greater in rats treated with 2,5-HD and MEK than in those treated with 2,5-HD alone (Ralston et al 1985). Urinary excretion of 2,5-HD increases in guinea pigs coadministered both MnBK and MEK (Couri et al 1978), but decreases in rats co-exposed to n-hexane and MEK (Iwata et al 1983(Iwata et al , 1984Shibata et al 1990a).…”

Section: Introductionmentioning

confidence: 97%

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Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Yu¹,

Hattis²,

Landaw³

et al. 2001

Arch Toxicol

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Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.

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Ketones of Four or Five Carbons

O’Donoghue

2023

Patty's Toxicology

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Several billion pounds of ketones are produced annually for industrial use in the United States and worldwide. Those with the highest production volumes include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, 4‐hydroxy‐4‐methyl‐2‐pentanone, isophorone, mesityl oxide, and acetophenone. Common methods used to manufacture ketones include aliphatic hydrocarbon oxidation, alcohol dehydration with subsequent oxidation, dehydrogenation of phenol, alkyl aromatic hydrocarbon oxidation, and condensation reactions. Ketones are commonly used in industry as solvents, extractants, chemical intermediates, and, to a lesser extent, flavor and fragrance ingredients. Although a common effect of excessive ketone exposure is CNS depression some ketones have pulmonary effects that are well below levels that cause acute CNS effects. For example, ketones such as diacetyl and chemically similar chemicals used for flavoring foods, coffee, and e‐cigarettes provide opportunities for widespread exposure and very debilitating pulmonary disease including bronchiolitis obliterans.

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Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone1, 2

Cited by 38 publications

References 17 publications

Acetone-induced changes in the toxicokinetics of 2,5-hexanedione in rabbits.

Acetone-induced changes in the toxicokinetics of 2,5-hexanedione in rabbits.

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Ketones of Four or Five Carbons

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