title: Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1.
abstract: Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Yeo
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ryu
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.forename: L Eric
authors.initials: LE
authors.lastname: Huang
authors.forename: Myung-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000740:Anemia / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009181:Mycoses / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D004921:Erythropoietin; D000666:Amphotericin B; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat