Comparative metabolism of bis(2-methoxyethyl) ether by rat and human hepatic microsomes: formation of 2-methoxyethanol.
Rat hepatic microsomes catalysed the NADPH-dependent cleavage of the central ether linkage of bis(2-methoxyethyl) ether (diglyme) yielding 2-methoxyethanol (2ME). Microsomes isolated from phenobarbital- or ethanol-pretreated rats exhibited an increased capacity to cleave diglyme to 2ME. This ethanol-induced increase in 2ME formation was not observed if incubations contained the cytochrome P450IIE1 inhibitor isoniazid. Pretreatment of rats with diglyme significantly increased microsomal P-450 levels, P-450-associated enzyme activities and the conversion of diglyme to 2ME. Following the diglyme pretreatment, an almost 30-fold increase in pentoxyresorufin dealkylase activity (P450IIB1/2) was evident in rat hepatic microsomes. Human hepatic microsomes also catalysed the NADPH-dependent cleavage of diglyme to 2ME. The formation of 2ME from diglyme correlated with the aniline hydroxylase activity (P450IIE1) levels measured in human hepatic microsomes. Studies using microsomes isolated from a cell line transfected with specific human P-450 cDNAs indicate that human CYP2E1 catalyses the conversion of diglyme to 2ME. These results suggest that the central ether linkage of diglyme is cleaved by rat and human P-450 and the specific involvement of hepatic P450IIE1 in this process is implicated.
Tirmenstein
M A
MA
Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Division of Biomedical and Behavioral Science, Cellular Toxicology Section, 4676 Columbia Parkway, Cincinnati, OH 45226, USA.