CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats

Suter-Eichenberger, R; Boelsterli, Urs A.; Conscience-Egli, M; Lichtensteiger, W.; Schlumpf, Margret

doi:10.1016/s0378-4274(00)00170-3

Cited by 9 publications

(2 citation statements)

References 29 publications

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“…There is also the potential for induction of CYP enzymes by VOCs, which would be especially relevant in the case of repeated daily exposures. Induction of CYP enzymes in neonatal rats has been reported in the case of musk xylene and toluene (Hansson et al, 1985;Suter-Eichenberger et al, 2000). In such studies, small but significant increases in liver size were also reported, which are likely to affect the metabolic capability of neonatal rats, as demonstrated in this particular study for PND10.…”

Section: Discussionsupporting

confidence: 62%

Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically Based Pharmacokinetic Modeling

Rodríguez

Mahle

Gearhart

et al. 2007

Toxicological Sciences

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The capability of physiologically based pharmacokinetic models to incorporate age-appropriate physiological and chemical-specific parameters was utilized to predict changes in internal dosimetry for six volatile organic compounds (VOCs) across different ages of rats. Typical 6-h animal inhalation exposures to 50 and 500 ppm perchloroethylene, trichloroethylene, benzene, chloroform, methylene chloride, or methyl ethyl ketone (MEK) were simulated for postnatal day 10 (PND10), 2-month-old (adult), and 2-year-old (aged) rats. With the exception of MEK, predicted venous blood concentrations of VOCs in the aged rat were equal or up to 1.5-fold higher when compared to the adult rat at both exposure levels, whereas levels were predicted to be up to 3.8-fold higher in the case of PND10 at 50 ppm. Predicted blood levels of MEK were similar in the adult and aged rat, but were more than 5-fold and 30-fold greater for PND10 rats at 500 and 50 ppm, respectively, reflecting high water solubility along with lower metabolic capability and faster ventilation rate per unit body weight (BW) of PND10 animals. Steady-state blood levels of VOCs, simulated by modeling constant exposure, were predicted to be achieved in the order PND10 > adult > aged, largely due to increasing fat volume. The dose metric, total amount metabolized per unit liver volume was generally much lower in PND10 than in adult rats. The blood:air partition coefficient, fat volume, and fat blood flow were identified as critical determinants for the predicted differences in venous blood concentrations between the adult and aged. The lower metabolic capability, largely due to a smaller liver size, and faster ventilation rate per unit BW of PND10 animals contribute the most to the differences between PND10 and adult rats. This study highlights the pharmacokinetic differences and the relevant parameters that may contribute to differential susceptibility to the toxic effects of VOCs across life stages of the rat.

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Section: Discussionsupporting

confidence: 62%

Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically Based Pharmacokinetic Modeling

Rodríguez

Mahle

Gearhart

et al. 2007

Toxicological Sciences

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“…Among the nitromusks, only MK had a minor inhibitory effect (31 ( 1%) when tested at a concentration of 100 µM, whereas MX was less effective (23 ( 10% inhibition). Interestingly, MX was reported to act as a CYP3A inducer in developing rats at postnatal day 14, but not in adult specimens, indicating differential sensitivity to MX in development (28). Other compounds have been shown to inhibit CYP3A catalyzed activities (progesterone 6Rhydroxylase and BFCOD activities) in carp and other fish species (29).…”

Section: Discussionmentioning

confidence: 99%

The Interference of Nitro- and Polycyclic Musks with Endogenous and Xenobiotic Metabolizing Enzymes in Carp: An In Vitro Study

Schnell

Martin-Skilton

Fernandes

et al. 2009

Environ. Sci. Technol.

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Synthetic musks are widely used as perfuming agents in products, such as cosmetics, detergents, and soaps. The increased detection of these substances in the aquatic environment and their high bioconcentration potential raises concerns about potential effects on aquatic species. This work aimed at assessing the interactions of the most widely used musks: nitromusks (musk xylene, musk ketone) and polycyclic musks (celestolide, galaxolide, and tonalide) with fish enzymatic systems involved in both xenobiotic and endogenous metabolism. Therefore, CYP catalyzed pathways were investigated in carp liver microsomes (CYP1A, CYP3A), ovarian microsomes (CYP19) and testicular mitochondria (CYP17 and CYP11beta) using standard substrates. Phase II activities (UDP-glucuronosyltransferases and sulfotransferases) were determined in carp liver microsomes and cytosol, respectively. Polycyclic musks (galaxolide and tonalide) were stronger inhibitors of CYP3A- (IC(50): 68-74 microM), CYP17- (IC(50): 213-225 microM), CYP11beta- and CYP19-catalyzed activities than nitromusks, while the latter showed higher ability to interfere with CYP1A (IC(50): 35-37 microM). The sulfation of estradiol was also significantly inhibited by tonalide and galoxolide (IC(50): 140-294 microM). Overall, polycyclic musks showed the highest potential to interfere with those activities involved in the synthesis and metabolism of steroids while nitromusks mainly interfered with xenobiotic metabolism (CYP1A-catalyzed reactions). The obtained data suggest that CYP isoforms are potentially sensitive targets of synthetic musk substances in fish.

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Occurrence and toxicity of musks and UV filters in the marine environment

Rainieri

Barranco

Primec

et al. 2017

Food and Chemical Toxicology

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CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats

Cited by 9 publications

References 29 publications

Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically Based Pharmacokinetic Modeling

Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically Based Pharmacokinetic Modeling

The Interference of Nitro- and Polycyclic Musks with Endogenous and Xenobiotic Metabolizing Enzymes in Carp: An In Vitro Study

Occurrence and toxicity of musks and UV filters in the marine environment

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