Biotransformation of [(12)C]- and [(13)C]-tert-amyl methyl ether and tert-amyl alcohol.
tert-Amyl methyl ether (TAME) is intended for use as a gasoline additive to increase oxygen content. Increased oxygen content in gasoline reduces tailpipe emissions of hydrocarbons and carbon monoxide from cars. Due to possible widespread use of TAME, the toxicity of TAME is under investigation. We studied the biotransformation of TAME in rats and one human volunteer after inhalation of (12)C- or (13)C-labeled TAME. In addition, the biotransformation of [(13)C]-tert-amyl alcohol was studied in rats after gavage. Urinary metabolites were identified by GC/MS and (13)C NMR. Rats (two males and two females) were individually exposed to 2000 ppm [(12)C]- or [(13)C]TAME for 6 h, and urine was collected for 48 h. Free and glucuronidated 2-methyl-2,3-butanediol and a glucuronide of tert-amyl alcohol were identified by (13)C NMR, GC/MS, and LC/MS/MS as major urinary metabolites on the basis of the relative intensities of the (13)C NMR signals. The presence of several minor metabolites was also indicated by (13)C NMR; they were identified as tert-amyl alcohol, 2-hydroxy-2-methylbutyric acid, and 3-hydroxy-3-methylbutyric acid. One human volunteer was exposed to an initial concentration of 27 000 ppm [(13)C]TAME by inhalation for 4 min from a 2 L gas sampling bag, and metabolites of TAME excreted in urine were analyzed by (13)C NMR. All TAME metabolites identified in rats were also present in the human urine samples. To study tert-amyl alcohol biotransformation, male rats (n = 3) were treated with 250 mg/kg [(13)C]-tert-amyl alcohol dissolved in corn oil by gavage, and urine was collected for 48 h. (13)C NMR of the urine samples showed the presence of metabolites identical to those in the urine of [(13)C]TAME-treated rats. Our results suggest that TAME is extensively metabolized by rats and humans to tert-amyl alcohol which may be further oxidized to diols and carboxylic acids. These reactions are likely mediated by cytochrome P450-dependent oxidations.
Amberg
A
A
Institut für Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Bernauer
U
U
Scheutzow
D
D
Dekant
W
W
D000280:Administration, Inhalation; D000393:Air Pollutants / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D005260:Female; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008738:Methyl Ethers / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D000439:Pentanols / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344
D000393:Air Pollutants; D008738:Methyl Ethers; D000439:Pentanols; C032765:tert-amyl alcohol; C096680:tertiary-amyl methyl ether