Interactive effects of methyl tertiary-butyl ether (MTBE) and tertiary-amyl methyl ether (TAME), ethanol and some drugs: Triglyceridemia, liver toxicity and induction of CYP (2E1, 2B1) and phase II enzymes in female Wistar rats

Abstract

The abilities of the gasoline additives methyl tert-butyl ether (MTBE) and tert-amyl methyl ether (TAME) to cause liver damage following oral administration, dosed alone or in combination with model hepatotoxins, were investigated in the rat. Inducibility of liver drug-metabolizing enzyme activities was also studied. Exposure to these ethers (10-20mmol/kg) for 3 days resulted in hepatomegaly (13-30%) and induction of cytochrome P450 (CYP) activity towards N-nitrosodimethylamine (NDMAD), 7-pentoxyresorufin (PROD), and 7-ethoxyresorufin (EROD). Immunoinhibition assays with monoclonal antibodies showed that the ethers were equipotent as inducers of CYP2E1 activity (2-fold increase) but not of CYP2B1, which was elevated up to 260-fold in TAME-treated rats but only by 20-fold in MTBE rats. A slight or no modifying effect was observed on the NADPH:quinone oxidoreductase (NQO1), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UGT) activities. Alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) were elevated in blood plasma after administration of the ethers. No dramatic enhancement of liver damage could be detected by plasma enzyme analysis (ALT, AST, alkaline phosphatase, γ-glutamyltransferase) following ether administration (13.5mmol/kg) to rats pretreated with mildly hepatotoxic dosages of ethanol, pyrazole, phenobarbital, acetaminophen (paracetamol), or 13-cis-retinoic acid (13-cis-RA or isotretinoin). Plasma triglycerides increased in TAME-treated rats (1.7-fold) and in all 13-cis-RA-treated groups (2.1-2.8-fold). The findings that MTBE and TAME exhibited a clear but differential inducing effect on two ether-metabolizing CYP forms (2E1 and 2B1) with no marked effect on phase II activities may reflect the importance of these pathways in vivo. The observation that only TAME by itself induced hypertriglyceridemia while acetaminophen- and 13-cis-RA-induced hypertriglyceridemia were aggravated by both ethers, points to differences in their effects on lipid metabolism. TAME was clearly a more potent CNS depressant than MTBE. There was no marked potentiation of drug/chemical-induced acute liver damage either by MTBE or TAME.