Cutaneous metabolism of glycol ethers

Lockley, David J.; Howes, D.; Williams, Faith M.

doi:10.1007/s00204-004-0619-3

Cited by 45 publications

(29 citation statements)

References 43 publications

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“…EGAEs can produce systemic toxicity, including spermatotoxic, teratogenic, and hematological effects, following oxidation to their corresponding aldehydes and alkoxyacetic acids (AAAs) by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), respectively [13,15]. These enzymes can metabolize EGAEs in the liver, skin and testis [13,[16][17][18]. The hematotoxicity studies of equimolar doses of BE, butoxyacetic aldehyde, and BAA revealed that the effects of all the three chemicals did not differ signifi cantly, which indicates that the interconversion of these chemicals is an effi cient metabolic process in vivo [13].…”

Section: Calculation Of Pka Log P and Log D Valuesmentioning

confidence: 99%

Comparison of the in Vitro Hemolytic Effects Produced by Alkoxyacetic Acids on Human and Rat Erythrocytes

Stárek¹,

Szabla²,

Kieć‐Kononowicz³

et al. 2008

International Journal of Occupational Medicine and Environmental Health

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Objectives: The alkoxyacetic acids (AAAs) are urinary metabolites of alkoxyethanol solvents. It is well documented that these chemicals can cause acute hemolytic anemia in humans and laboratory animals. There are scarce data on the relative hemolytic activity of these acids. Likewise, information is lacking on the relationship between their hemolytic activity and physicochemical properties. The aim of this study was to compare the hemolytic activity of fi ve AAAs in red blood cells (RBCs) derived from donors' blood and male Wistar rats. Moreover, the possible relationship between lipophilic and hemolytic activity of AAAs was also investigated. Materials and Methods: The RBCs washed in TRIS buffer, pH 7.4, were adjusted to a packed cell volume (PCV) of about 20% and incubated in a water bath at 37°C for 0-3 h in the presence of different concentrations of AAAs. The hemolytic effects, in terms of the changes in RBCs, PCV, mean corpuscular volume (MCV) and free hemoglobin (HGB free ) in incubation medium, were evaluated. Based on the dose-response relationship for RBCs, PCV and MCV, the effective concentration values (EC 50 ) and their 95% confi dence intervals (95% CI) were calculated. The octanol-water partition coeffi cient (log P) and distribution coeffi cient (log D) of AAAs were computed using PALLAS software. The correlation between log P and log D values for AAAs at pH 7.4 and their EC 50 was analyzed. Results: Human RBCs were 1.9-3.1 times more resistant to the hemolytic activity of AAAs than rat erythrocytes. Also, the hemolytic activity of individual AAAs did not differ considerably; the maximum differences ranging from 2.0 to 3.3. The EC 50 values of AAAs highly correlated with their log P and log D values. Conclusions: The relatively small differences between the hemolytic effects of AAAs on rat and human erythrocytes may be associated with the strong acidity and relatively similar lipophilicity of these chemicals.

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Section: Calculation Of Pka Log P and Log D Valuesmentioning

confidence: 99%

Comparison of the in Vitro Hemolytic Effects Produced by Alkoxyacetic Acids on Human and Rat Erythrocytes

Stárek¹,

Szabla²,

Kieć‐Kononowicz³

et al. 2008

International Journal of Occupational Medicine and Environmental Health

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“…The explanation the biological basis of the interactions between ethanol and EGAEs may be related to the metabolism of these compounds. The glycol ethers, especially EE, BE, and 2-phenoxyethanol, are metabolized in vitro by rat hepatic and cutaneous cytosolic preparations in the reaction involving ADH and ALDH in both tissues [35]. Hepatic cytosol metabolizes ethanol in preference to intermediate chainlength EGAEs, whereas the skin cytosol preferentially metabolizes the glycol ethers.…”

Section: Discussionmentioning

confidence: 99%

“…The rates of ADH oxidation by rat liver cytosol were the greatest for ethanol followed by EE and BE. In contrast, the order of metabolism by rat skin cytosolic fraction was changed to BE > EE > ethanol [35]. Although skin contains enzymes that have the capacity to biotransformation EGAEs localized in the basal layer of the epidermis [36], the physicochemical properties of these compounds result in rapid penetration and distinct reduction in dermal metabolism during their percutaneous absorption [37].…”

Section: Discussionmentioning

confidence: 99%

Interactive effect of combined exposure to ethylene glycol ethers and ethanol on hematological parameters in rats

Stárek¹,

Miranowicz-Dzierżawska²,

Starek‐Świechowicz³

2010

Health

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The study of the interaction of three glycol ethers, i.e. 2-methoxyethanol (ME), 2-ethoxyethanol (EE) and 2-butoxyethanol (BE) administered subcutaneously for 4 weeks and ethanol simultaneously given as 10% w/v solution for drinking in male rats, was carried out from a toxicodynamic point of view. Administered alone, ME (2.5 and 5.0 mM/kg), EE (2.5 and 5.0 mM/kg) or BE (0.75 and 1.25 mM/kg) resulted in a decrease of red blood cells (RBC), packed cell volumes (PCV), and hemoglobin concentration (HGB), as well as an increase in mean corpuscular volume (MCV) and reticulocyte count (Ret). In the rats co-exposed to ethanol and EGAEs, a significantly less pronounced hematological changes in comparison with animal exposed to these ethers alone were seen. The rats simultaneously exposed to ethanol and both ME and EE at the lower dose demonstrated mainly protection from the alterations in leukocyte system. In contrast, in the rats which consumed ethanol and were simultaneously treated with the higher dose of ME or EE (5.0 mM/kg) the amelioration of same hematological parameters were displayed. The intake of ethanol along with BE treatment at both doses resulted in markedly ameliorated hematological parameters, compared to those which were changed by BE alone. In conclusion, the decrease of the hemolytic effects of EGAEs is ethanol dependent. Ethanol is a substrate of alcohol dehydrogenase (ADH), and affinity of this enzyme to ethanol is greater than that to glycol ethers. It is possible that ethanol results in the change in EGAEs metabolism.

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“…40 In addition, it has been shown that the potential for first-pass dermal metabolism during absorption is reduced if the physicochemical properties of the chemical enable rapid penetration. 41 …”

Section: Skin Metabolismmentioning

confidence: 99%

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

DumontCoralie

PrietoPilar

AsturiolDavid

et al. 2015

Applied In Vitro Toxicology

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The exposure of the skin to consumer products, drugs, and environmental chemicals can result in their penetrating the skin barrier and entering systemic circulation, potentially resulting in adverse effects in the skin and other organs. The assessment of dermal penetration and bioavailability (including penetration, metabolism, and entry into the systemic circulation) is therefore an important consideration in the risk assessment of chemicals. The skin is a heterogeneous organ with a multilayer structure. Based on its architecture and physiology, substances can penetrate through three major ways but can also be blocked in the different skin layers and in the skin appendages, which act as reservoir. In addition to that, as the skin is a metabolically competent organ, substances can undergo metabolism. After a brief description of the skin architecture, this review will focus on the skin penetration mechanisms and skin metabolic capacities. The skin absorption has traditionally been tested in vivo on animals. However, with the new legislation (i.e., Registration, Evaluation, Authorisation, and Restriction of Chemicals Regulation or Cosmetics Regulation), alternatives to animal testing have to be implemented. In a second part, this review will provide a description of the main in vitro and in silico or computational models available to study skin absorption and skin metabolism (i.e., ex vivo skin models, artificial membrane barriers, primary cells and cell lines, Quantitative Structure-Activity Relationship [QSAR], simulators for the prediction of skin metabolism).

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Cutaneous metabolism of glycol ethers

Cited by 45 publications

References 43 publications

Comparison of the in Vitro Hemolytic Effects Produced by Alkoxyacetic Acids on Human and Rat Erythrocytes

Comparison of the in Vitro Hemolytic Effects Produced by Alkoxyacetic Acids on Human and Rat Erythrocytes

Interactive effect of combined exposure to ethylene glycol ethers and ethanol on hematological parameters in rats

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

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