Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats

作者：Barrett Terrance D^*; Palomino Heather L; Brondstetter Theresa I; Kanelakis Kimon C; Wu Xiaodong; Yan Wen; Merton Katherine P; Schoetens Freddy; Ma Jing Ying; Skaptason Judy; Gao Jingjin; Da Thao Tran; Venkatesan Hariharan; Rosen Mark D; Shankley Nigel P; Rabinowitz Michael H

来源：British Journal of Pharmacology, 2015, 172(16): 4078-4088.

DOI：10.1111/bph.13188

Background and PurposeSmall-molecule inhibitors of prolyl hydroxylase (PHD) enzymes are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bioavailable, the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated.
Experimental ApproachJNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action was compared with rhEPO in healthy rats and in a rat model of inflammation-induced anaemia and FID [peptidoglycan-polysaccharide (PGPS) model].
Key ResultsOral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, and increased plasma EPO. Repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). The serum iron concentration was increased with low doses (0.3mg<bold>kg(</bold>-1)) but reduced at high doses (6mg<bold>kg(</bold>-1)). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia, as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS-treated rats.
Conclusions and ImplicationsPHD inhibition has a beneficial effect on iron metabolism in addition to stimulating the release of EPO. Small-molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID.

• 出版日期2015-8