Acetone compared to other ketones in modifying the hepatotoxicity of inhaled 1,2-dichlorobenzene in rats and mice

Brondeau, M. T.; Ban, M.; Bonnet, Pierre; Guenier, J. P.; Céaurriz, J. de

doi:10.1016/0378-4274(89)90103-3

Cited by 21 publications

(5 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Until now, no changes had been observed in CYP isozyme profiles after MEK inhalation (Toftgard et al 1981), and only few studies had shown that MEK could induce microsomal liver enzymes in rats after acute oral exposure (Robertson et al, 1989;Raunio et al, 1990;ATSDR, 1992) or after acute inhalation of high MEK concentrations (≥ 1500 ppm) (Brondeau et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of inhaled methylethylketone in rats

Cosnier

Grossmann

Nunge

et al. 2017

Drug and Chemical Toxicology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolism of inhaled methylethylketone in rats

Cosnier

Grossmann

Nunge

et al. 2017

Drug and Chemical Toxicology

View full text Add to dashboard Cite

show abstract

“…Rat P4502E1 would thus not be explicitly involved in the formation of reactive metabolites. However, it has been shown in vivo that 1,2-DCB-induced hepatotoxicity is potentiated by acetone and other low molecular weight ketones, which are associated with induction of P4502E1 (27). Possibly rat P4502E1, a significant constitutive enzyme, is involved in the oxidation of both the 3,4-and 4,5-site of the molecule, to the same extent.…”

Section: Discussionmentioning

confidence: 99%

Differences in Cytochrome P450-Mediated Biotransformation of 1,2-Dichlorobenzene by Rat and Man: Implications for Human Risk Assessment

Hissink

Oudshoorn²,

Ommen³

et al. 1996

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The oxidative biotransformation of 1,2-dichlorobenzene (1,2-DCB) was investigated using hepatic microsomes from male Wistar, Fischer-344 and Sprague-Dawley (SD) rats, phenobarbital (PB)- and isoniazid (ISO) pretreated male Wistar rats and from man. In addition, microsomes from cell lines selectively expressing one cytochrome P450 (P4502E1, 1A1, 1A2, 2B6, 2C9, 2D6, /A6 and 3A4) were used. The rate of conversion was 0.09 nmol/min/mg. protein for both Wistar and Fischer-344 rat microsomes, 0.04 for SD-microsomes and 0.14 for human microsomes. Induction of Wistar rats with isoniazid (ISO, a P4502E1 inducer) or phenobarbital (PB, a P4502B1/2 inducer) resulted in an increased conversion rate of 0.20 and 0.42 nmol/min/mg. protein, respectively. Covalent binding of radioactivity to microsomal protein was similar for Wistar, Fischer and ISO-pretreated rats (16-17% of total metabolites), whereas induction with PB resulted in an increased covalent binding of 23% of total metabolites. Covalent binding was 31% for SD-microsomes and only 4.6% for human microsomes. Ascorbic acid notably reduced the amount of covalently bound metabolites for the SD-microsomes only, indicating that for these microsomes quinones were likely to be involved in this part of the covalent binding. Conjugation of epoxides with glutathione (GSH) inhibited most of the covalent binding for all microsomes. In the absence of GSH, the epoxides were hydrolyzed by epoxide hydrolase, resulting in the formation of dihydrodiols. Inhibition of epoxide hydrolase resulted in a decreased conversion and an increased covalent binding for all microsomes tested, indicating a role of epoxides in the covalent binding. Fischer-344 rat liver microsomes showed a lower epoxide hydrolase activity than microsomes from Wistar and Sprague-Dawley rats, which may explain the higher sensitivity to 1,2-DCB induced hepatotoxicity of Fischer rats in vivo. Conjugation of the epoxides with GSH was predominantly non-enzymatic for the rat, whereas for man, conjugation was nearly exclusively catalyzed by glutathione-S-transferases. This difference may be explained by the formation of a 'non-reactive' 3,4-epoxide by P4502E1 in human microsomes: incubations with microsomes selectively expressing human P4502E1 as well as human liver microsomes, resulted in the formation of similar amounts of 2,3- and 3,4-dichlorophenol (DCP), as well as two GSH-epoxide conjugates in equal amounts. For rat microsomes, one major GSH-epoxide conjugate was found, and a much higher covalent binding, particularly for the PB-microsomes. Therefore, we postulate that rat P4502B1/2 preferentially oxidizes the 4,5-site of 1,2-DCB, resulting in a reactive epoxide. Postulating these epoxides to be involved in the mechanism(s) of toxicity, human risk after exposure to 1,2-DCB will be overestimated when risk assessment is solely based on toxicity studies conducted in rat.

show abstract

“…Preexposure to MIBK enhanced the DCB-induced increase in serum GLDH activity, whereas the increases in cytochrome P-450 content and GST activity were identical to those resulting from exposure to MIBK alone. In mice, MIBK interacted with DCB on centrolobular liver G-6-Pase (Brondeau et al 1989).…”

Section: Effect Of Mibk On the Hepatotoxicity Of Other Agents 12-dicmentioning

confidence: 98%

“…Transient narcosis was observed during the first 4 weeks of treatment with the highest dose (100 mg/ kg) (CMA 1981). Brondeau et al (1989) investigated the effect of MIBK on the hepatotoxicity of inhaled 1,2-dichlorobenzene (DCB) using male Sprague-Dawley rats and OF1 mice. The aim of this study was to compare the interactive liver responses of MIBK with DCB and to explain them in terms of metabolic changes.…”

Section: Chronic Intraperitoneal Toxicitymentioning

confidence: 99%

Safety Assessment of MIBK (Methyl Isobutyl Ketone)1

Johnson¹

2004

Int J Toxicol

View full text Add to dashboard Cite

MIBK (Methyl Isobutyl Ketone) is an aliphatic ketone that functions as both a denaturant and solvent in cosmetic products. Current use in cosmetic products is very limited, but MIBK is reported to be used in one nail correction pen (volume = 3 ml) at a concentration of 21%. The maximum percutaneous absorption rate in guinea pigs is 1.1 µmol/min/cm 2 at 10 to 45 min. Metabolites include 4-hydroxy-4-methyl-2-pentanone (oxidation product) and 4-methyl-2-pentanol (4-MPOL) (reduction product). Values for the serum half-life and total clearance time of MIBK in animals were 66 min and 6 h, respectively. In clinical tests, most of the absorbed MIBK had been eliminated from the body 90 min post exposure. MIBK was not toxic via the oral or dermal route of exposure in acute, short-term, or subchronic animal studies, except that nephrotoxicity was observed in rats dosed with 1 g/kg in a short-term study. MIBK was an ocular and skin irritant in animal tests. Ocular irritation was noted in 12 volunteers exposed to 200 ppm MIBK for 15 min in a clinical test. A depression of the vestibulo-oculomotor reflex was seen with intravenous infusion of MIBK (in an emulsion)at 30 µM/kg/min in female rats. The no-observed-effect level in rats exposed orally to MIBK was 50 mg/kg. Both gross and microscopic evidence of lung damage were reported in acute inhalation toxicity studies in animals. Short-term and subchronic inhalation exposures (as low as 100 ppm) produced effects in the kidney and liver that were species and sex dependent. Dermal doses of 300 or 600 mg/kg for 4 months in rats produced reduced mitotic activity in hair follicles, increased thickness of horny and granular cell layers of the epidermis, a decrease in the number of reactive centers in follicles (spleen), an increase in the number of iron-containing pigments in the area of the red pulp (spleen), and a reduction in the lipid content of the cortical layer of the adrenal glands. Neuropathological changes in the most distal portions of the tibial and ulnar nerves were observed in young adult rats which inhaled 1500 ppm MIBK for up to 5 months. No adverse effects were seen in any other neurological end point by any route of exposure in other studies using rats or other animal species. Clinical tests demonstrated a threshold for MIBK-induced irritation of the lungs at 0.03 to 0.1 mg/L after 1 min of respiration. MIBK was not mutagenic in the Ames test or in a mitotic gene-conversion assay in bacteria. Mammalian mutagenicity test results were also negative in the following assays: mouse lymphoma, unscheduled DNA synthesis, micronucleus, cell transformation, and chromosome damage. MIBK did not induce any treatment-related increases in embryotoxicity or fetal malformations in pregnant Fischer 344 rats or CD-1 mice that inhaled MIBK at concentrations of 300, 1000, or 3000 ppm. There was evidence of treatment-related maternal toxicity only at the highest concentration tested. MIBK applied to the tail of rats daily at doses of 300 or 600 mg/kg for 4 months produced changes in the t...

show abstract

Acetone compared to other ketones in modifying the hepatotoxicity of inhaled 1,2-dichlorobenzene in rats and mice

Cited by 21 publications

References 18 publications

Metabolism of inhaled methylethylketone in rats

Metabolism of inhaled methylethylketone in rats

Differences in Cytochrome P450-Mediated Biotransformation of 1,2-Dichlorobenzene by Rat and Man: Implications for Human Risk Assessment

Safety Assessment of MIBK (Methyl Isobutyl Ketone)1

Contact Info

Product

Resources

About