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 Blood, 1 February 2006, Vol. 107, No. 3, pp. 916-923.
Prepublished online as a Blood First Edition Paper on September 27, 2005; DOI 10.1182/blood-2005-06-2564.

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HEMATOPOIESIS

Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1

Eun-Jin Yeo, Ji-Hye Ryu, Young-Suk Cho, Yang-Sook Chun, L. Eric Huang, Myung-Suk Kim, and Jong-Wan Park

From the Department of Pharmacology and the Department of Physiology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; and the Laboratory of Human Carcinogenesis, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD.

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-1{alpha}, 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-1{alpha}, 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.


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