Metabolism of inhaled methylethylketone in rats

Abstract

Methylethylketone (MEK) is widely used in industry, often in combination with other compounds. Although nontoxic, it can make other chemicals harmful. This study investigates the fate of MEK in rat blood, brain and urine as well as its hepatic metabolism following inhalation over 1 month (at 20, 200 or 1400 ppm). MEK did not significantly accumulate in the organism: blood concentrations were similar after six-hour or 1-month inhalation periods, and brain concentrations only increased slightly after 1 month's exposure. Urinary excretion, based on the major metabolites, 2,3-butanediols (± and meso forms), accounted for less than 2.4% of the amount inhaled. 2-Butanol, 3-hydroxy-2-butanone and MEK itself were only detectable in urine in the highest concentration conditions investigated, when metabolic saturation occurred. Although MEK exposure did not alter the total cytochrome P450 concentration, it induced activation of both CYP1A2 and CYP2E1 enzymes. In addition, the liver glutathione concentration (reduced and oxidized forms) decreased, as did glutathione S-transferase (GST) activity (at exposure levels over 200 ppm). These metabolic data could be useful for pharmacokinetic model development and/or verification and suggest the ability of MEK to influence the metabolism (and potentiate the toxicity) of other substances.

Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

“…At the cytosolic level, except for a slight decrease in activity in animals exposed to MEK200 and MEK1400 (Cosnier et al, 2017), GST activity was not altered by the other exposure conditions (1629 ± 334 U/g protein on average).…”

“…The increase in the blood burden of both solvents could be due to inhibitory action of the co-solvent on the activity of the CYP enzyme family since the total CYP concentration was unaltered in these exposure conditions. However, the activities of CYP1A2 and CYP2E1, the isoforms specifically involved in TOL (and MEK) metabolization (ATSDR, 2015, Cosnier et al, 2017, were systematically higher in exposed animals than in controls. No additive or synergistic induction was detected (even after 1-month exposure) in the presence of MEK.…”

“…All of the potential urinary biomarkers of TOL (hippuric acid (HA), o,m,p-cresols, BMA and o,m,p-toluylmercapturic acids) and MEK (2-butanol, 3-hydroxy-2-butanone and 23BDs) were investigated for this study. Based on previous results, some were already known to be poor biomarkers due to their low specificity or high endogenous excretion (for example hippuric acid, m,p-cresols or 2-butanol) (Ikeda et al, 2008, Cosnier et al, 2013, Cosnier et al, 2017. In a co-exposure context, HA also failed to highlight interaction between TOL and MEK at exposure levels below the 8h-OEL (Ukai et al, 1994, Uaki et al, 1995.…”

“…Similarly, the presence of TOL modified the MEK blood concentration, which increased significantly for MEK20 and MEK200 co-exposures in the presence of TOL500 ( Figure 2b). We were unable to fit the data corresponding to the blood MEK concentrations (MEK-Blood) plotted against atmospheric MEK (MEK-A) concentrations (Cosnier et al, 2017). The majority of the data points for TOL were above the first bisector (Figure 3a), thus indicating that TOL-Brain concentrations were higher than TOL-Blood.…”

“…The different urinary metabolites -ortho-cresol (oCre) and benzylmercapturic acid (BMA) for TOL, and 2,3-butanediols (±23BD and meso23BD) for MEK -were measured as previously described (Cosnier et al, 2012, Cosnier et al, 2013, Cosnier et al, 2017.…”