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

Sumner, Susan; Asgharian, Bahman; Moore, Timothy A.; Parkinson, Horace D.; Bobbitt, Carol M.; Fennell, Timothy R.

doi:10.1002/jat.929

Cited by 7 publications

(8 citation statements)

References 12 publications

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“…It is likely that similar enzymatic steps to those for the other ethers are involved, with tert-amyl alcohol (TAA) being a central metabolite. Hydroxylation of the latter would result in three possible diol products, two of which could be further oxidized to carboxylic acids (2,49). However, not all of these enzymatic steps involved in fuel oxygenate degradation have been identified unambiguously and characterized thoroughly.…”

mentioning

confidence: 99%

Formation of Alkenes via Degradation of tert -Alkyl Ethers and Alcohols by Aquincola tertiaricarbonis L108 and Methylibium spp

Schäfer

Muzica

Schuster

et al. 2011

Appl Environ Microbiol

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Bacterial degradation pathways of fuel oxygenates such as methyl tert-butyl and tert-amyl methyl ether (MTBE and TAME, respectively) have already been studied in some detail. However, many of the involved enzymes are still unknown, and possible side reactions have not yet been considered. In Aquincola tertiaricarbonis L108, Methylibium petroleiphilum PM1, and Methylibium sp. strain R8, we have now detected volatile hydrocarbons as by-products of the degradation of the tert-alkyl ether metabolites tert-butyl and tert-amyl alcohol (TBA and TAA, respectively). The alkene isobutene was formed only during TBA catabolism, while the beta and gamma isomers of isoamylene were produced only during TAA conversion. Both tert-alkyl alcohol degradation and alkene production were strictly oxygen dependent. However, the relative contribution of the dehydration reaction to total alcohol conversion increased with decreasing oxygen concentrations. In restingcell experiments where the headspace oxygen content was adjusted to less than 2%, more than 50% of the TAA was converted to isoamylene. Isobutene formation from TBA was about 20-fold lower, reaching up to 4% alcohol turnover at low oxygen concentrations. It is likely that the putative tert-alkyl alcohol monooxygenase MdpJ, belonging to the Rieske nonheme mononuclear iron enzymes and found in all three strains tested, or an associated enzymatic step catalyzed the unusual elimination reaction. This was also supported by the detection of mdpJK genes in MTBE-degrading and isobutene-emitting enrichment cultures obtained from two treatment ponds operating at Leuna, Germany. The possible use of alkene formation as an easy-to-measure indicator of aerobic fuel oxygenate biodegradation in contaminated aquifers is discussed.The extensive use of methyl tert-butyl ether (MTBE) and related compounds as fuel oxygenates has resulted in contamination of numerous groundwater sites in the United States and Europe (13,26,33,51). Although MTBE is now banned in some countries and may be phased out in others (52), it will persist at polluted sites for a long time due to its poor biodegradability. Despite this enormous environmental prevalence, only a few strains capable of growth on MTBE, ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME) have been found, and fuel oxygenate metabolism has not been elucidated in full detail (20,30,31,46). Since the pioneering works of Salanitro et al. and Steffan et al. (42,43,48), it is generally agreed that aerobic MTBE degradation proceeds via a monooxygenase-catalyzed ether cleavage resulting in formation of tert-butyl alcohol (TBA). The latter is hydroxylated to the corresponding diol, 2-methyl-1,2-propanediol (MPD), which is further oxidized to 2-hydroxyisobutyric acid (2-HIBA). This branched carboxylic acid is then introduced into common metabolic routes after isomerization to 3-hydroxybutyric acid (39). Since ETBE shares the tert-butyl structure with MTBE, it should have a similar degradation path via TBA (8, 30). The biochemistry of TAME catabol...

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confidence: 99%

Formation of Alkenes via Degradation of tert -Alkyl Ethers and Alcohols by Aquincola tertiaricarbonis L108 and Methylibium spp

Schäfer

Muzica

Schuster

et al. 2011

Appl Environ Microbiol

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“…994-05-8, 98%) was supplied by Chevron Research and Technology Company (Richmond, CA). Both 1 H-and 13 C-NMR analyses of TAME were consistent with the chemical structure (Sumner et al, 2003a). Gas chromatography analysis indicated >98% purity for the test material.…”

Section: Chemicalsmentioning

confidence: 54%

“…0, 4, 8, 16 and 24 h after exposure termination (time points for blood collections were staggered between rats). At the end of each 6-h nose-only exposure, four additional rats and four additional mice were sacrificed immediately for determination of the total retained [ 14 C]TAME equivalents (Sumner et al, 2003a). In addition, following inhalation exposure and gavage administration of [ 14 C]TAME, four rats and four mice were transported to glass metabolism cages for the collection of urine (over dry ice, 0-8, 8-24 and 24-48 h), feces (0-24 and 24-48 h), exhaled volatile organics (two charcoal traps in series) and 14 CO 2 (0-1, 1-3, 3-6, 6-8, 8-24 and 24-48 h) after termination of exposure (Sumner et al, 2003b).…”

Section: Collection Of Samplesmentioning

confidence: 99%

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Species and gender differences in the metabolism and distribution of tertiary amyl methyl ether in male and female rats and mice after inhalation exposure or gavage administration

Sumner

Janszen

Asgharian

et al. 2003

J of Applied Toxicology

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Tertiary amyl methyl ether (TAME) is a gasoline fuel additive used to reduce emissions. Understanding the metabolism and distribution of TAME is needed to assess potential human health issues. The effect of dose level, duration of exposure and route of administration on the metabolism and distribution of TAME were investigated in male and female F344 rats and CD-1 mice following inhalation or gavage administration. By 48 h after exposure, >96% of the administered radioactivity was expired in air (16-71%) or eliminated in urine and feces (28-72%). Following inhalation exposure, mice had a two- to threefold greater relative uptake of [14C]TAME compared with rats. Metabolites were excreted in urine of rats and mice that are formed by glucuronide conjugation of tertiary amyl alcohol (TAA), oxidation of TAA to 2,3-dihydroxy-2-methylbutane and glucuronide conjugation of 2,3-dihydroxy-2-methylbutane. A saturation in the uptake and metabolism of TAME with increased exposure concentration was indicated by a decreased relative uptake of total [14C]TAME equivalents and an increase in the percentage expired as volatiles. A saturation of P-450 oxidation of TAA was indicated by a disproportional decrease of 2,3-dihydroxy-2-methylbutane and its glucuronide conjugate with increased exposure concentration.

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“…However, in contrast to 2-methylpropan-1,2-diol formation from TBA, the hydroxylation of TAA would result in three possible diol products (Fig. 1), as has already been shown for TAME and TAA conversion in rats and humans (2,43). The 1,2-and 1,3-diols could be further oxidized to 2-hydroxy-2-methyl-and 3-hydroxy-3-methylbutyric acids, respectively, while the dehydrogenation of the 2,3-diol would result in the formation of methylacetoin.…”

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confidence: 62%

Bacterial Degradation of tert-Amyl Alcohol Proceeds via Hemiterpene 2-Methyl-3-Buten-2-ol by Employing the Tertiary Alcohol Desaturase Function of the Rieske Nonheme Mononuclear Iron Oxygenase MdpJ

Schuster

Schäfer

Hübler

et al. 2011

Journal of Bacteriology

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Tertiary alcohols, such as tert-butyl alcohol (TBA) and tert-amyl alcohol (TAA) and higher homologues, are only slowly degraded microbially. The conversion of TBA seems to proceed via hydroxylation to 2-methylpropan-1,2-diol, which is further oxidized to 2-hydroxyisobutyric acid. By analogy, a branched pathway is expected for the degradation of TAA, as this molecule possesses several potential hydroxylation sites. In Aquincola tertiaricarbonis L108 and Methylibium petroleiphilum PM1, a likely candidate catalyst for hydroxylations is the putative tertiary alcohol monooxygenase MdpJ. However, by comparing metabolite accumulations in wild-type strains of L108 and PM1 and in two mdpJ knockout mutants of strain L108, we could clearly show that MdpJ is not hydroxylating TAA to diols but functions as a desaturase, resulting in the formation of the hemiterpene 2-methyl-3-buten-2-ol. The latter is further processed via the hemiterpenes prenol, prenal, and 3-methylcrotonic acid. Likewise, 3-methyl-3-pentanol is degraded via 3-methyl-1-penten-3-ol. Wild-type strain L108 and mdpJ knockout mutants formed isoamylene and isoprene from TAA and 2-methyl-3-buten-2-ol, respectively. It is likely that this dehydratase activity is catalyzed by a not-yet-characterized enzyme postulated for the isomerization of 2-methyl-3-buten-2-ol and prenol. The vitamin requirements of strain L108 growing on TAA and the occurrence of 3-methylcrotonic acid as a metabolite indicate that TAA and hemiterpene degradation are linked with the catabolic route of the amino acid leucine, including an involvement of the biotin-dependent 3-methylcrotonyl coenzyme A (3-methylcrotonyl-CoA) carboxylase LiuBD. Evolutionary aspects of favored desaturase versus hydroxylation pathways for TAA conversion and the possible role of MdpJ in the degradation of higher tertiary alcohols are discussed.

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

Cited by 7 publications

References 12 publications

Formation of Alkenes via Degradation of tert -Alkyl Ethers and Alcohols by Aquincola tertiaricarbonis L108 and Methylibium spp

Formation of Alkenes via Degradation of tert -Alkyl Ethers and Alcohols by Aquincola tertiaricarbonis L108 and Methylibium spp

Species and gender differences in the metabolism and distribution of tertiary amyl methyl ether in male and female rats and mice after inhalation exposure or gavage administration

Bacterial Degradation of tert-Amyl Alcohol Proceeds via Hemiterpene 2-Methyl-3-Buten-2-ol by Employing the Tertiary Alcohol Desaturase Function of the Rieske Nonheme Mononuclear Iron Oxygenase MdpJ

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