title: Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment.
abstract: Hereditary tyrosinemia type 1 (HT1) is a recessive disease caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) that catalyzes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. In mice models of HT1, FAH deficiency causes death within the first 24h after birth. Administration of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC) prevents neonatal death in HT1 mice, ameliorates the HT1 phenotype but does not prevent development of hepatocellular carcinoma later on. FAA has been shown to deplete cells of glutathione by forming adducts. We tested whether a combination of a cell membrane permeable derivative of glutathione, glutathione monoethylester (GSH-MEE) and vitamin C could provide an alternative effective treatment for HT1. GSH-MEE (10 mmol/kg/j)/vitamin C (0.5 mmol/kg/j) treatment was given orally to pregnant/nursing female mice. While FAH-/- pups died in absence of treatment, all FAH-/- pups survived the critical first 24h of life when the mothers were on the GSH-MEE/vitamin C treatment and showed normal growth until postnatal day 10 (P10). However, after P10, pups showed failure to thrive, lethargy and died around P17. Thus, GSH-MEE/vitamin C supplementation could rescue the mice model of HT1 from neonatal death but it did not prevent the appearance of a HT1 phenotype in the second week after birth.
authors.affiliation: Laboratory of Cellular and Developmental Genetics, CREFSIP, Department of Medicine, Pav. C-E Marchand, 1030 Av. De la Médecine, Université Laval, Que., Canada G1K 7P4.
authors.forename: Chantale
authors.initials: C
authors.lastname: Langlois
authors.forename: Rossana
authors.initials: R
authors.lastname: Jorquera
authors.forename: Diana
authors.initials: D
authors.lastname: Orejuela
authors.forename: Anne
authors.initials: A
authors.lastname: Bergeron
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: William J
authors.initials: WJ
authors.lastname: Rhead
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000517:prevention & control; D003512:Cyclohexanones / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology; D018384:Oxidative Stress; D011247:Pregnancy; D020176:Tyrosinemias / Q000401:mortality / Q000517:prevention & control*
chemical_list: D000975:Antioxidants; D003512:Cyclohexanones; D009579:Nitrobenzoates; C042431:S-ethyl glutathione; D006867:Hydrolases; C020156:fumarylacetoacetase; D005978:Glutathione; C077073:nitisinone; D001205:Ascorbic Acid