title: Mutagenicity studies of methyl-tert-butylether using the Ames tester strain TA102.
abstract: Methyl-tert-butylether (MTBE) is an oxygenate widely used in the United States as a motor vehicle fuel additive to reduce emissions and as an octane booster [National Research Council, Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fules, National Academy Press, Washington, DC, 1996]. But it is the potential for MTBE to enter drinking water supplies that has become an area of public concern. MTBE has been shown to induce liver and kidney tumors in rodents but the biochemical process leading to carcinogenesis is unknown. MTBE was previously shown to be non-mutagenic in the standard Ames plate incorporation test with tester strains that detect frame shift (TA98) and point mutations (TA100) and in a suspension assay using TA104, a strain that detects oxidative damage, suggesting a non-genotoxic mechanism accounts for its carcinogenic potential. These strains are deficient in excision repair due to deletion of the uvrB gene. We hypothesized that the carcinogenic activity of MTBE may be dependent upon a functional excision repair system that attempts to remove alkyl adducts and/or oxidative base damage caused by direct interaction of MTBE with DNA or by its metabolites, formaldehyde and tert-butyl alcohol (TBA), established carcinogens that are mutagenic in some Ames strains. To test our hypothesis, the genotoxicity of MTBE-induced DNA alterations was assayed using the standard Ames test with TA102, a strain similar to TA104 in the damage it detects but uvrB + and, therefore, excision repair proficient. The assay was performed (1) with and without Aroclor-induced rat S-9, (2) with and without the addition of formaldehyde dehydrogenase (FDH), and (3) with human S-9 homogenate. MTBE was weakly mutagenic when tested directly and moderately mutagenic with S-9 activation producing between 80 and 200 TA102 revertants/mg of compound. Mutagenicity was inhibited 25%-30% by FDH. TA102 revertants were also induced by TBA and by MTBE when human S-9 was substituted for rat S-9. We conclude that MTBE and its metabolites induce a mutagenic pathway involving oxidation of DNA bases and an intact repair system. These data are significant in view of the controversy surrounding public safety and the environmental release of MTBE and similar fuel additives.
authors.affiliation: USC-Norris Comprehensive Cancer Center, University of Southern California Cancer Research Laboratory, Los Angeles 90089-9270, USA. donna@hsc.usc.edu
authors.forename: D
authors.initials: D
authors.lastname: Williams-Hill
authors.forename: C P
authors.initials: CP
authors.lastname: Spears
authors.forename: S
authors.initials: S
authors.lastname: Prakash
authors.forename: G A
authors.initials: GA
authors.lastname: Olah
authors.forename: T
authors.initials: T
authors.lastname: Shamma
authors.forename: T
authors.initials: T
authors.lastname: Moin
authors.forename: L Y
authors.initials: LY
authors.lastname: Kim
authors.forename: C K
authors.initials: CK
authors.lastname: Hill
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004269:DNA, Bacterial / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005798:Genes, Bacterial / Q000187:drug effects; D006801:Humans; D008738:Methyl Ethers / Q000633:toxicity*; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D012486:Salmonella typhimurium / Q000145:classification / Q000187:drug effects* / Q000235:genetics
chemical_list: D000393:Air Pollutants; D002273:Carcinogens; D004269:DNA, Bacterial; D008738:Methyl Ethers; D009153:Mutagens; C043243:methyl tert-butyl ether; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent