Metabolism of methyl tert-butyl ether and other gasoline ethers in mouse liver microsomes lacking cytochrome P450 2E1

Hong, Jun-Yan; Wang, Yongyu; Bondoc, Flordeliza Y.; Yang, Chung S.; Gonzalez, Frank J.; Pan, Zhenyi; Cokonis, Clara-Dina; Hu, Wen‐Yu; Bao, Ziping

doi:10.1016/s0378-4274(98)00389-0

Cited by 26 publications

(9 citation statements)

References 11 publications

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“…(1997) reported the estimated volume of distribution at steady state ( V dss ), ranging from 0.67 to 1.3 l kg −1 after TBA IV administration, which indicates distribution outside the central compartment and is not consistent with protein binding. Unlike MTBE, there is in vitro evidence that ETBE is metabolized by CYP2B1 (Turini et al ., 1998) with a study in P450 2E1 knockout mice showing that this enzyme has a negligible contribution (Hong et al ., 1999b). As such, ETBE was modeled in the liver as Michaelis–Menten kinetics via one pathway rather than two.…”

Section: Discussionmentioning

confidence: 99%

“…The metabolism of both ETBE and TBA was assumed the same in male rats as in female rats. In a change from the MTBE model, the metabolism of ETBE to TBA was modeled in the liver as Michaelis–Menten kinetics via one pathway rather than two, a model supported by selected in vitro studies (Hong et al ., 1999a, 1999b; Le Gal et al ., 2001; Turini et al ., 1998). The V max and K m for the low‐affinity, high‐capacity pathway of MTBE metabolism were used for the single metabolic pathway for ETBE.…”

Section: Methodsmentioning

confidence: 99%

“…Cytochrome P450 metabolic oxidation is commonly associated with vulnerability to high‐dose metabolic saturation. Several lines of evidence support ETBE being metabolized by liver P450 enzymes in humans (CYP2A6) (Hong et al ., 1999a; Le Gal et al ., 2001) and rats (CYP2B1) (Turini et al ., 1998) and a study in P450 2E1 knockout mice showed that this enzyme has a negligible contribution (Hong et al ., 1999b). The two main metabolic products derived from the metabolism of ETBE's major metabolite, TBA, are 2‐methyl‐1,2‐propanediol and α‐hydroxyisobutyric acid (Bernauer et al ., 1998), both of which have been detected in the urine of rats and humans exposed to ETBE (Amberg et al ., 1999).…”

Section: Introductionmentioning

confidence: 99%

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Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Borghoff

Ring

Banton

et al. 2016

J of Applied Toxicology

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In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary‐butyl ether (ETBE), caused liver tumors in male rats, while tertiary‐butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary‐butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat‐specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male‐rat‐specific mode of action for TBA‐induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Borghoff

Ring

Banton

et al. 2016

J of Applied Toxicology

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“…The unlabeled CH 3 protons from the TAME-derived portion of the metabolite were located as a broad singlet at 1.3 ppm. Signals for protons directly attached to labeled carbons were centered at 1.3 ppm (CH 3 ) TAME by liver microsomes from 2E1 knockout mice indicated that CYP 2E1 plays a negligible role in the metabolism of these compounds (Hong et al, 1999). No studies have been conducted to elucidate the mechanism for the conversion of tertiary butyl alcohol (TBA) or TAA to the oxidation products methyl propanediol or 2,3-dihydroxy-2-methylbutane, respectively.…”

Section: Metabolite 3 (Peak 2)mentioning

confidence: 99%

Characterization of metabolites and disposition of tertiary amyl methyl ether in male F344 rats following inhalation exposure

Sumner

Asgharian

Moore

et al. 2003

J of Applied Toxicology

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Tertiary amyl methyl ether (TAME) is a fuel additive used to reduce carbon monoxide in automobile emissions. Because of the potential for human exposure, this study was conducted to develop methods for the characterization and quantitation of metabolites in expired air and excreta of rats exposed to a mixture of [13C]- and [14C]TAME ([2,3,4-13C]- and [2-14C]2-methoxy-2-methylbutane). The distribution of TAME in rats was determined following inhalation exposure, and TAME-derived metabolites were characterized in expired air and urine. Male rats were exposed for 6 h via nose-only inhalation to 2500 ppm [14C/13C]TAME, and expired air, urine and feces were collected for up to 7 days. Over 95% of the total recovered radioactivity was excreted by 48 h after exposure. Recovered radioactivity was expired as organic volatiles (44%) and 14CO2 (3%) and excreted in urine (51%) and feces (1%). Both TAME and its metabolite tertiary amyl alcohol (TAA) accounted for > or =90% of the radiolabel in expired air 0-8 h following exposure termination. Three major urinary metabolites of TAME were identified: (1) a direct glucuronide conjugate of TAA; (2) a product of oxidation at the methylene carbon of TAA (2,3-dihydroxy-2-methylbutane); (3) a glucuronide conjugate of metabolite 2. Metabolite 1 accounted for most of the TAME-derived metabolites excreted 0-8 h following exposure termination. Further metabolic products of TAA (metabolites 2 and 3) accounted for most of the excreted TAME-derived metabolites at later time points.

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“…The positive effects of MTBE include a reduction in particulate emissions, unburnt hydrocarbons, CO and exhaust emissions. However, both the pollution of the environment by MTBE and the possible adverse effects of exposure to MTBE are of public concern (Johanson et al, 1995;Lacy et al, 1995;Brown, 1997;Lillquist and Zeigle, 1998;Nihlen et al, 1998;Hong et al, 1999;Deeb et al, 2001). Johanson et al (1995) measured the blood, water, and olive oil/air partition coefficients in vitro of MTBE, ETBE, TAME and tertiary butyl alcohol (TBA), a metabolite of MTBE and ETBE.…”

Section: Introduction and A Brief Review Of Decomposition Of Air Toximentioning

confidence: 99%

Decomposition of Methyl Tert-Butyl Ether by Adding Hydrogen in a Cold Plasma Reactor

Hsieh

Tsai

Chang

et al. 2011

Aerosol Air Qual. Res.

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Methyl tert-butyl ether (MTBE) is extensively used as an oxygenate and octane enhancer in gasoline. Its release to the environment has generated great public and governmental concern. In this study, we give a brief review of the decomposition of air toxics by the application of radio frequency (RF) plasma reactors and then present our study on decomposition of methyl tert-butyl ether by adding hydrogen in a cold plasma reactor. Based on our references, there are four types of the application in the RF plasma reactors are discussed, including: (i) Application I.: Converting methane, decomposing carbon dioxide, ethoxyethane, and ethylene oxide; (ii) Application II.: Decomposing methyl chloride, 1,1-C 2 H 2 Cl 2 , and CH 2 Cl 2 ; (iii) Application III.: Decomposing dichlorodifluoromethane, CHF 3 , CH 2 F 2 , CCl 2 F 2 , and BF 3 ; (iv) Application IV.: Decomposing dichlorodifluoromethane, CH 3 SH, CS 2 , SF 6 , and SF 6 + H 2 S mixture. Moreover, this study demonstrates the feasibility of applying a radio frequency (RF) plasma reactor for decomposing and converting MTBE. Experimental results indicate that the decomposition efficiency (η MTBE ) and the fraction of total input carbon converted into CH 4 , C 2 H 2 and C 2 H 4 (F CH4+C2H2+ C2H4 ) increased with the input power and decreased as both the H 2 /MTBE ratio and the MTBE influent concentration in the MTBE/H 2 /Ar plasma environment increased. Interestingly, applying radio frequency plasma to the decomposition of MTBE while adding hydrogen constitutes alternative method of decomposing and converting MTBE into CH 4 , C 2 H 4 , C 2 H 2, iso-butane and iso-butene.

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Metabolism of methyl tert-butyl ether and other gasoline ethers in mouse liver microsomes lacking cytochrome P450 2E1

Cited by 26 publications

References 11 publications

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Characterization of metabolites and disposition of tertiary amyl methyl ether in male F344 rats following inhalation exposure

Decomposition of Methyl Tert-Butyl Ether by Adding Hydrogen in a Cold Plasma Reactor

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