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17199 
Technical Report 
HEI 
Human cytochrome P450 isozymes in metabolism and health effects of gasoline ethers 
Hong, JY; Wang, YY; Mohr, SN; Bondoc, FY; Deng, C 
2001 
1 
Research Reports (Health Effects Institute)
ISSN: 1041-5505
EISSN: 2688-6855 
Health Effects Institute 
Cambridge, MA 
Metabolism of ether oxygenates added to gasoline 
102 
7-28 
English 
11504148 
To reduce the production of carbon monoxide and other pollutants in motor vehicle exhaust, methyl tert-butyl ether (MTBE*), ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME) are added to gasoline as oxygenates for more complete combustion. Among them, MTBE is the most widely used. The possible adverse effect of MTBE in humans is a public concern, but the human enzymes responsible for metabolism of these gasoline ethers and the causes or factors for increased sensitivity to MTBE in cer-tain individuals are totally unknown. This information is important to understanding the health effects of MTBE in humans and to assessing the human relevance of pharma-cokinetics and toxicity data obtained from animals. In the present study, we demonstrated that human liver is active in metabolizing MTBE to tert-butyl alcohol (TBA), a major circulating metabolite and an exposure marker of MTBE. The activity is localized in the microsomal fraction but not in the cytosol. Formation of TBA in human liver microsomes is NADPH-dependent and is significantly inhibited by carbon monoxide, which inhibits cytochrome P450 (CYP) enzymes. These results provide strong evi-dence that CYP enzymes play a critical role in the metabo-lism of MTBE in human livers. Human liver is also active in the oxidative metabolism of 2 other gasoline ethers, ETBE and TAME. We observed a large interindividual vari-ation in metabolizing these gasoline ethers in 15 microsomal samples prepared from normal human livers. The activity level (pmol metabolite/min/mg) ranged from 204 to 2,890 for MTBE; 179 to 3,134 for ETBE; and 271 to 8,532 for TAME. The microsomal activities in metabo-lizing MTBE, ETBE, and TAME correlated highly with each other (r = 0.91 to 0.96), suggesting that these ethers are metabolized by the same enzyme(s). 
Health Effects Institute Research Report