Metabolic interactions

There are 3 major metabolic interactions of MEK: potentiation of hexacarbon neuropathy and haloalkane toxicity, and inhibition of alcohol metabolism.

Potentiation of hexacarbon neuropathy

It is well recognised that MEK can potentiate the neurotoxicity of some other solvents. Consequently, chronic exposure to such a solvent, even at low concentrations, with concurrent exposure to methyl ethyl ketone may result in neuropathy. MEK is not itself neurotoxic.

MEK was first suspected of potentiating the neurotoxic effects of n-hexane after neuropathy was reported in 18 glue-sniffers following a formulation change. The glue had contained 31% n-hexane but neuropathy only developed after the concentration was reduced to 16% and MEK was added to the product. No further cases were reported after the MEK was removed (Altenkirch et al., 1978).

Animal studies have shown that co-exposure to 2,5-hexanedione (the neurotoxic metabolite of n-hexane) and methyl ethyl ketone results in more rapid onset of neurotoxicity than administration of 2,5-hexanedione alone (Ralston et al., 1985). The serum and nerve concentrations of 2,5-hexanedione were significantly increased in rats treated with 2,5-hexanedione in combination with methyl ethyl ketone compared to 2,5-hexanedione alone. The effect was strongest with methyl ethyl ketone compared with acetone or toluene (Zhao et al., 1998).

The mechanism of this phenomenon is unclear, it is not thought to be due to 2,5-hexanedione alone (Shibata et al., 1990). It may be due to induction of the hepatic mixed function oxidase system (Topping et al., 2001). In a toxicokinetic study of human volunteers, co-exposure to MEK had little effect on n-hexane toxicokinetics. However, there was a decrease in the rate of formation of 2,5-hexanedione suggesting inhibition of the metabolism of n-hexane (van Engelen et al., 1997). In contrast, workers exposed simultaneously to MEK and n-hexane had increased urinary excretion of 2,5-hexanedione (Cardona et al., 1993). In animals the concentration of urinary n-hexane metabolites depended on the exposure concentrations of MEK involved. The concentration of the main n-hexane metabolites, 2,5-hexanedione and 2-hexanol decreased as the MEK concentration increased (Shibata et al., 1990). However, a more recent study demonstrated that although urinary concentrations of 2,5-hexanedione decreased in the short-term with co-exposure to MEK, the concentration of 2,5-hexanedione actually increased with more prolonged exposure (Ichihara et al., 1998).

• Methyl n-butyl ketone

Methyl n-butyl ketone has the same neurotoxic metabolite as n-hexane, 2,5-hexanedione. Animal studies have shown that co-exposure to methyl ethyl ketone increases the neurotoxicity of methyl n-butyl ketone (Saida et al., 1976). In animal studies, co-administration of methyl n-butyl ketone and methyl ethyl ketone resulted in increased serum concentrations of methyl n-butyl ketone (Abdel-Rahman et al., 1976). In rats, inhalation of a methyl n-butyl ketone and methyl ethyl ketone mixture caused a significant reduction in the sleep times induced by hexobarbital (hexobarbitone), an enzyme-inducing drug (Couri et al., 1977; Couri et al., 1978). Methyl n-butyl ketone alone did not alter sleep times. Hepatic microsomal enzyme activities were increased in the methyl n-butyl ketone/methyl ethyl ketone exposed group (Couri et al., 1977).

Potentiation of haloalkane toxicity

• Carbon tetrachloride

MEK has been shown to potentiate the hepatotoxicity of carbon tetrachloride in rats. This may have been due to the metabolites, 2,3-butanediol and/or 3-hydroxy-2-butanone (Dietz and Traiger, 1979).

• Chloroform

MEK has also been show to potentiate the hepatotoxicity and nephrotoxicity of chloroform in rats. The extent of liver and renal injury was dose related and at the highest dose there was a reduction in the degree of potentiation. The mechanism of potentiation is unknown, but at high doses the ketone may reduce the metabolism of chloroform and so reduce toxicity. Alternatively, high doses of ketones may damage the cells in such a way as to reduce the toxicity of chloroform (Brown and Hewitt, 1984).

Inhibition of alcohol metabolism

Ethanol appears to inhibit microsomal oxidation of MEK. In a volunteer study, ingestion of ethanol and inhalation of MEK resulted in increased MEK concentrations in the blood, suggesting that ethanol inhibits MEK metabolism. When the ethanol was ingested before the inhalation exposure to MEK, the blood concentration of MEK remained high throughout the exposure. When ethanol was given after cessation of MEK exposure a higher MEK blood concentration was seen in the elimination phase. The concentration of the metabolite 2-butanol was increased almost 10 times in the presence of ethanol. The higher blood concentration of MEK in the presence of ethanol was reflected in increased exhalation and urinary excretion of MEK. The elimination of MEK through the lungs was 8% in the presence of ethanol compared to 3% without ethanol. The elimination of MEK in the urine doubled with co-exposure to ethanol but was still less than 1% of the absorbed dose (Liira et al., 1990a).

Animal studies have also demonstrated that concomitant MEK exposure slows the metabolism of ethanol (Cunningham et al., 1989) and other studies have shown that MEK increases microsomal activity (Couri et al., 1977) and inhibits alcohol dehydrogenase (Cunningham et al., 1989).

MEK may have inhibited methanol metabolism following ingestion of approximately 240 ml of an ink cleaning solution thought to contain 47% MEK and 45% methanol. There was minimal metabolism of methanol to formate despite a high methanol concentration (2020 mg/l; 63 mmol/l) and the anion gap remained normal. MEK probably acted by inhibiting alcohol dehydrogenase (Price et al., 1994).

Other interactions

In volunteer studies exposure to a mixture of MEK and acetone had no effect on neurobehavioural performance. MEK does not potentiate the effect of acetone and there is no pharmacokinetic interaction between the two ketones (Brown et al., 1987; Dick et al., 1988; Dick et al., 1989).

In a volunteer study investigating solvent exposure and pyschomotor performance, neither MEK or toluene had any effect. In addition, in a mixed exposure neither solvent had any potentiation effects on the other (Dick et al., 1984). Workers exposed simultaneously to methyl ethyl ketone and toluene had reduced urinary excretion of 2,5-hexanedione (Cardona et al., 1993).

Toxicology of Solvents • Xylene

MEK appears to inhibit the metabolism of xylene, possibly by interaction with the initial monooxygenase-catalysed step of biotransformation. In volunteers exposed to m-xylene and MEK, the blood xylene concentration increased almost two-fold compared to the concentration following exposure to xylene alone. Although the clearance of m-xylene and excretion of its metabolite, methyl hippuric acid, were reduced, there appeared to be no effect on the biotransformation of MEK. Exposure to MEK 20 hours before exposure to m-xylene did not affect xylene metabolism (Liira et al., 1988b).

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