Comparative metabolism of Bis(2-methoxyethyl) ether by rat and human hepatic microsomes: formation of 2-methoxyethanol

Details

• Personal Author:
  Tirmenstein MA
• Description:
  The characteristics of the metabolism of bis(2-methoxyethyl)ether (111966) (diglyme) to 2-methoxyethanol (109864) (2ME) were explored in this study. Male Sprague-Dawley-rats were pretreated with phenobarbital (PB), beta-naphthoflavone (beta-NF), ethanol, or diglyme and were then sacrificed. Hepatic microsomes were isolated and incubated. In microsomal incubations containing an NADPH generating system, three major metabolites were detected; 2ME, 2-(2- methoxyethoxy)ethanol (111773), and an unknown compound. In analysis of microsomes of untreated rats, less than 2% of the added diglyme was metabolized after 30 minutes. The activity of aniline- hydroxylase, a cytochrome-P-450 inducer, increased following ethanol pretreatment. The activities of various cytochrome-P-450 enzymes, as well as the metabolism of diglyme, increased with PB or ethanol pretreatment. Pretreatment with diglyme increased microsomal levels of cytochrome-P-450 by 70% over control microsomes. 2ME formation was dependent on both the incubation time and the concentration of microsomal proteins present. Various cytochrome-P-450 inhibitors reduced the metabolism of diglyme. The inhibitor isoniazid specifically inhibited the isozyme P450IIE1, even in diglyme or ethanol pretreated microsomes. Human hepatic microsomes also metabolized the NADPH dependent breakdown of diglyme to 2ME. A significantly positive correlation was found between aniline- hydroxylase activity and 2ME formation in both rats and humans. Due to the extensive increases in metabolism after pretreatment with diglyme, diglyme was implicated as an inducer of cytochrome-P-450. The authors conclude that the central ether linkage of diglyme is cleaved by ethanol, PB and isozymes of cytochrome-P-450, most notably P450IIE1. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Enzymes Glycols Laboratories Occupational Health Safety
• Keywords:
  Cell-metabolism Enzyme-activity Hepatic-microsomal-enzymes Laboratory-animals Liver-cells Metabolic-study NIOSH-Author
• ISSN:
  0887-2333
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DBBS - Division of Biomedical and Behavioral Sciences
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  7
• Issue:
  5
• NIOSHTIC Number:
  nn:00232196
• Citation:
  Toxicol In Vitro 1993 Sep; 7(5):645-652
• Contact Point Address:
  M. A. Tirmenstein, 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
• CAS Registry Number:
  2-Methoxyethanol (CAS RN 109-86-4) ; Diethylene glycol monomethyl ether (CAS RN 111-77-3) ; Diglyme (CAS RN 111-96-6)
• Federal Fiscal Year:
  1993
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology in Vitro
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:fb6a7daa5b7456d25a4b8a2eeb14329a15148833a47138c6dab17b9606945de451e1a8bb242946e7087f16e9422330c999f49c4644a82d951ba4bc82aeda91c2
• Download URL:
  https://stacks.cdc.gov/view/cdc/204363/cdc_204363_DS1.pdf
• File Type:
  [PDF - 735.73 KB ]