title: Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy.
abstract: Liver failure is often accompanied by cognitive impairment and coma, a syndrome known as hepatic encephalopathy (HE). The administration of flumazenil, a benzodiazepine (BZ) antagonist, is effective in reversing the symptoms of HE in many patients. These clinical observations gave rise to notions of an endogenous BZ-like mechanism in HE, but to date no viable candidate compounds have been characterized. We show here that the hemoglobin (Hb) metabolites hemin and protoporphyrin IX (PPIX) interact with the BZ site on the gamma-aminobutyric acid (GABA(A)) receptor and enhance inhibitory synaptic transmission in a manner similar to diazepam and zolpidem. This finding suggests that hemin and PPIX are neuroactive porphyrins capable of acting as endogenous ligands for the central BZ site. The accumulation of these porphyrins under pathophysiologic conditions provides a potentially novel mechanism for the central manifestations of HE.
authors.affiliation: Graduate Program in Neuroscience, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ruscito
authors.forename: Neil L
authors.initials: NL
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004594:Electrophysiology / Q000379:methods; D005442:Flumazenil / Q000494:pharmacology; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D006454:Hemoglobins; D011524:Protoporphyrins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D006427:Hemin; C028025:protoporphyrin IX