Rat olfactory mucosa displays a high activity in metabolizing methyl tert-butyl ether and other gasoline ethers

Abstract

Methyl tert-butyl ether (MTBE) is a widely used gasoline oxygenate. Two other ethers, ethyl tert-butyl ether (ETBE) and tert-amyl methyl ether (TAME), are also used in reformulated gasoline. Inhalation is a major route for human exposure to MTBE and other gasoline ethers. The possible adverse effects of MTBE in humans are a public concern and some of the reported symptoms attributed to MTBE exposure appear to be related to olfactory sensation. In the present study, we have demonstrated that the olfactory mucosa of the male Sprague-Dawley rat possesses the highest microsomal activities, among the tissues examined, in metabolizing MTBE, ETBE, and TAME. The metabolic activity of the olfactory mucosa was 46-fold higher than that of the liver in metabolizing MTBE, and 37- and 25-fold higher, respectively, in metabolizing ETBE and TAME. No detectable activities were found in the microsomes prepared from the lungs, kidneys, and olfactory bulbs of the brain. The observations that the metabolic activity was localized exclusively in the microsomal fraction, depended on the presence of NADPH, and was inhibitable by carbon monoxide are consistent with our recent report on MTBE metabolism in human and mouse livers (Hong et al., 1997) and further confirm that cytochrome P450 enzymes play a critical role in the metabolism of MTBE, ETBE, and TAME. The apparent K(m) and Vmax values for the metabolism of MTBE, ETBE, and TAME in rat olfactory microsomes were very similar, ranging from 87 to 125 microM and 9.8 to 11.7 nmol/min/mg protein, respectively. Addition of TAME (0.1 to 0.5 mM) into the incubation mixture caused a concentration-dependent inhibition of the metabolism of MTBE and ETBE. Coumarin (50 microM) inhibited the metabolism of these ethers by approximately 87%. Further comparative studies with human nasal tissues on the metabolism of these ethers are needed in order to assess the human relevance of our present findings.