Ketone potentiation of haloalkane‐induced hepato‐ and nephrotoxicity. II. implication of monooxygenases

Raymond, Pierre; Plaa, Gàbriel L.

doi:10.1080/15287399509532038

Cited by 18 publications

(5 citation statements)

References 31 publications

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“…These two compounds are known inductors of the isoform 2E1 of the CYP 450 [8,9,19]. Chloroform nephrotoxicity is enhanced by pretreatment with acetone [20]. The possibility that the increased toxicity of xenobiotics in animals exposed translactionally to ethanol was due to induction of CYP 450 2E1 was suggested by Chhabra et al [21] in Sprague-Dawley rats.…”

Section: Discussionmentioning

confidence: 99%

Increase in the Renal Damage Induced by Paracetamol in Rats Exposed to Ethanol Translactationally

Llamas

Martínez²,

Jaramillo-Juárez³

et al. 1998

Neonatology

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Administration of ethanol (8%) or acetone (1%) to nursing dams in the drinking water, for 10 days, increased the nephrotoxicity of paracetamol (APAP) in the 14-day-old lactating offspring. The percentage of proximal tubular cells with evidence of necrotic damage in male rats was higher in those animals that received APAP (500 mg/kg, i.p.) and whose nursing rats were exposed to ethanol (25.0 ± 8.4%) or acetone (17.2 ± 1.2%), than in the group treated with APAP alone (10.6 ± 1.6%). The activity of urinary N-acetylglucuronidase was also significantly higher in the rats exposed translactationally to ethanol or acetone than in animals treated with the APAP alone. Nephrotoxicity showed a sexual dimorphic pattern with a higher toxicity in male than in female rats. The percentage of necrotic tubules in the male rats not exposed to inductor was 10.6 ± 1.6%, and in female rats 5.0 ± 1.4% (p < 0.05). Animals exposed to ethanol or acetone and treated with APAP showed less weight gain than the group treated only with APAP. Our results suggest that renal toxicity is enhanced in the nursing animals that were exposed, via maternal milk, to ethanol or acetone (inductors of cytochrome P₄₅₀2E1), than in the control animals. This circumstance may be relevant in alcoholic women while they are lactating.

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Section: Discussionmentioning

confidence: 99%

Increase in the Renal Damage Induced by Paracetamol in Rats Exposed to Ethanol Translactationally

Llamas

Martínez²,

Jaramillo-Juárez³

et al. 1998

Neonatology

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“…The letter metabolite was not detected with oral administration [ 852 , 854 ]. MIBK has been shown to induce liver and renal CYPs, potentiating hepato- and nephrotoxicity produced by chloroform and carbon tetrachloride [ 853 , 855 , 856 ].…”

Section: Epigenetic Carcinogens or Carcinogens With Uncertain Mode Of...mentioning

confidence: 99%

“…MoA underlying hepatocarcinogenicity of MIBK in mice is not well understood. While it potentiated hepatotoxicity and cholestasis produced by other chemicals [ 853 , 855 , 856 , 859 , 860 ] no evidence of hepatotoxicity was observed when MIBK was administered alone [ 275 , 843 ]. A study by Hughes and colleagues [ 861 ] suggested involvement of receptor-mediated mechanism, specifically, activation of the CAR/PXR nuclear receptors, which results in hepatocellular proliferation consequently leading to tumor development.…”

Section: Epigenetic Carcinogens or Carcinogens With Uncertain Mode Of...mentioning

confidence: 99%

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

Kobets

Smith

Williams

2022

Foods

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Commonly consumed foods and beverages can contain chemicals with reported carcinogenic activity in rodent models. Moreover, exposures to some of these substances have been associated with increased cancer risks in humans. Food-borne carcinogens span a range of chemical classes and can arise from natural or anthropogenic sources, as well as form endogenously. Important considerations include the mechanism(s) of action (MoA), their relevance to human biology, and the level of exposure in diet. The MoAs of carcinogens have been classified as either DNA-reactive (genotoxic), involving covalent reaction with nuclear DNA, or epigenetic, involving molecular and cellular effects other than DNA reactivity. Carcinogens are generally present in food at low levels, resulting in low daily intakes, although there are some exceptions. Carcinogens of the DNA-reactive type produce effects at lower dosages than epigenetic carcinogens. Several food-related DNA-reactive carcinogens, including aflatoxins, aristolochic acid, benzene, benzo[a]pyrene and ethylene oxide, are recognized by the International Agency for Research on Cancer (IARC) as causes of human cancer. Of the epigenetic type, the only carcinogen considered to be associated with increased cancer in humans, although not from low-level food exposure, is dioxin (TCDD). Thus, DNA-reactive carcinogens in food represent a much greater risk than epigenetic carcinogens.

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“…According to Raymond and Plaa (1995a), the oral administration to male rats of 1362 mg/kg MIBK in 5% polyoxyethylated castor oil produced increased renal cytochrome P-450 and aniline hydroxylase activity and increased liver and renal aminopyrine N-demethylase activity. No histopathology was noted.…”

Section: Effect On Enzyme Activitymentioning

confidence: 99%

Safety Assessment of MIBK (Methyl Isobutyl Ketone)1

Johnson¹

2004

Int J Toxicol

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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...

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Ketone potentiation of haloalkane‐induced hepato‐ and nephrotoxicity. II. implication of monooxygenases

Cited by 18 publications

References 31 publications

Increase in the Renal Damage Induced by Paracetamol in Rats Exposed to Ethanol Translactationally

Increase in the Renal Damage Induced by Paracetamol in Rats Exposed to Ethanol Translactationally

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

Safety Assessment of MIBK (Methyl Isobutyl Ketone)1

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