Biotransformation of methyl tert-butyl ether by human cytochrome P450 2A6

Shamsipur, Mojtaba; Beigi, Ali Akbar Miran; Teymouri, Mohammad; Poursaberi, Tahereh; Mostafavi, Seyed Mojtaba; Soleimani, Parviz; Chitsazian, Fereshteh; Tash, Shahram Abolhassan

doi:10.1007/s10532-011-9510-0

Cited by 23 publications

(19 citation statements)

References 21 publications

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“…These findings are consistent with those of Bernauer and co-workers ( 43 ) and indicate that the metabolic pathway in humans is the same as in rats. Shamsipur and coworkers ( 45 ) characterized the metabolic biotransformation of MTBE by human CYP2A6. Their results indicated that the first measurable metabolite was tert-butanol.…”

Section: Resultsmentioning

confidence: 99%

Permitted Daily Exposure for Diisopropyl Ether as a Residual Solvent in Pharmaceuticals

Romanelli¹,

Evandri

2018

ToxicolRes

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Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the “Guideline Q3C (R6) on impurities: guideline for residual solvents” issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which “no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found”. We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of 356 mg/m3 (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions.

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Section: Resultsmentioning

confidence: 99%

Permitted Daily Exposure for Diisopropyl Ether as a Residual Solvent in Pharmaceuticals

Romanelli¹,

Evandri

2018

ToxicolRes

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“…We then started to find out what is necessary in order to develop a new scale since for any future study; the entrepreneurship scale would be the owner of researcher.We analysed a number of scientific study regarding scale development. The study gained momentum upon obtaining the required authorizations (Al-Khalifah, 2018;Shamsipur et al, 2012;Mostafavi et al, 2017). A format was determined for the format of scale, and a pool comprised of items and questions were developed.…”

Section: Scale Development Processmentioning

confidence: 99%

Development of Entrepreneurship Scale Towards University Students

Nurluöz¹

2019

R SAN

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The aim of this study is to develop a reliable and valid measurement tool to evaluate the entrepreneurship characteristics of university students. The study group is comprised of 386 students at the Faculty of Nursing, Near East University. Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were applied in order to assess the construct validity of entrepreneurship scale. Prior to the application of Exploratory Factor analysis, Kolmogrov Smirnov, Shapiro Wilks tests were applied in order to identify whether the data set shows normal distribution; QQ plot was analysed with regard to the distribution and the skewness and kurtosis values of distribution were checked accordingly. In consideration with the generated results, the data set was considered as showing normal distribution. Upon ensuring the normality assumption required for the Exploratory Factor analysis, Kaiser-Mayer-Olkin (KMO) coefficient and Barlett sphericity test that are used in the identification of data eligibility for the Exploratory Factor Analysis were applied respectively. The findings with regard to the reliability of scale were ensured with Cronbach Alpha (internal consistency). The findings showed that the reliability coefficient for internal consistency is sufficient. It is concluded that our study can be used in scientific researches since it was checked in terms of validity and reliability.

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“…High levels of MTBE are encountered during motor vehicle refueling, where attendants and customers are exposed to evaporated emissions ( 5 , 6 ). MTBE is readily absorbed when inhaled or ingested ( 7 ) with the metabolic pathways underlying this involving oxidative demethylation of MTBE to formaldehyde and tert -butanol by microsomal cytochrome P450 enzymes ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

An investigation of methyl tert-butyl ether-induced cytotoxicity and protein profile in Chinese hamster ovary cells

Xie¹,

Hong²,

Zhou³

et al. 2017

Molecular Medicine Reports

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Methyl tert-butyl ether (MTBE) is widely used as an oxygenating agent in gasoline to reduce harmful emissions. However, previous studies have demonstrated that MTBE is a cytotoxic substance that has harmful effects in vivo and in vitro. Although remarkable progress has been made in elucidating the mechanisms underlying the MTBE-induced reproductive toxicological effect in different cell lines, the precise mechanisms remain far from understood. The present study aimed to evaluate whether mammalian ovary cells were sensitive to MTBE exposure in vitro by assessing cell viability, lactate dehydrogenase (LDH) leakage, malondialdehyde (MDA) content and antioxidant enzyme activities. In addition, the effect of MTBE exposure on differential protein expression profiles was examined by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. MTBE exposure induced significant effects on cell viability, LDH leakage, plasma membrane damage and the activity of antioxidant enzymes. In the proteomic analysis, 24 proteins were demonstrated to be significantly affected by MTBE exposure. Functional analysis indicated that these proteins were involved in catalytic activity, binding, structural molecule activity, metabolic processes, cellular processes and localization, highlighting the fact that the cytotoxic mechanisms resulting from MTBE exposure are complex and diverse. The altered expression levels of two representative proteins, heat shock protein family A (Hsp70) members 8 and 9, were further confirmed by western blot analysis. The results revealed that MTBE exposure affects protein expression in Chinese hamster ovary cells and that oxidative stress and altered protein levels constitute the mechanisms underlying MTBE-induced cytotoxicity. These findings provided novel insights into the biochemical mechanisms involved in MTBE-induced cytotoxicity in the reproductive system.

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Biotransformation of methyl tert-butyl ether by human cytochrome P450 2A6

Cited by 23 publications

References 21 publications

Permitted Daily Exposure for Diisopropyl Ether as a Residual Solvent in Pharmaceuticals

Permitted Daily Exposure for Diisopropyl Ether as a Residual Solvent in Pharmaceuticals

Development of Entrepreneurship Scale Towards University Students

An investigation of methyl tert-butyl ether-induced cytotoxicity and protein profile in Chinese hamster ovary cells

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