title: Regulation of the glyoxalase pathway in human brain microvascular endothelium: effects of troglitazone and tertiary butylhydroperoxide.
abstract: The glyoxalase system, comprised of glyoxalase-I and glyoxalase-II with glutathione as the cofactor, plays an important role in the detoxification of methylglyoxal and other alpha-oxo-aldehydes. Such aldehydes, which increase with hyperglycemia, give rise to advanced glycation end products. The objective of this research was to examine the glyoxalase system in human cerebromicrovascular cells. The hypothesis tested was that this pathway would be regulated by phase 2 enzyme inducers such as t-butylhydroquinone and modulated by the insulin-sensitizing drug troglitazone. Human cerebromicrovascular endothelial cells were cultured and exposed to varying concentrations of t-butylhydroquinone or troglitazone. The activity of glyoxylase-I in human endothelial cells was similar to the activity present in hepatocytes. The phase 2 enzyme inducer t-butylhydroquinone had no effect on the glyoxalase enzymes activities but significantly increased glutathione levels and glutathione reductase activity, indicating that phase 2 enzyme inducers might promote alpha-oxo-aldehyde scavenging. Troglitazone decreased the activities of glyoxalase-I and -II and decreased glyoxalase-I mRNA. Troglitazone had no effect on glutathione levels or on the activity of glutathione reductase or glutathione peroxidase. We conclude that phase 2 enzyme inducers may promote scavenging of alpha-oxoaldehydes in endothelial cells.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: G F
authors.initials: GF
authors.lastname: Davies
authors.forename: W J
authors.initials: WJ
authors.lastname: Roesler
authors.forename: B H J
authors.initials: BH
authors.lastname: Juurlink
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000502:physiology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D000077288:Troglitazone; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology; D000099301:Hydroxyacylglutathione Hydrolase
chemical_list: D002839:Chromans; D005978:Glutathione; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D007791:Lactoylglutathione Lyase; D011765:Pyruvaldehyde; D013844:Thiazoles; D045162:Thiazolidinediones; D013869:Thiolester Hydrolases; D000077288:Troglitazone; D020122:tert-Butylhydroperoxide; D000099301:Hydroxyacylglutathione Hydrolase