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Toxins 2013, 5(8), 1475-1485; doi:10.3390/toxins5081475
Article

Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease

1,†,* , 1,†, 1,†, 1, 1, 1, 2, 2, 3, 1 and 1
1 Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan 2 Department of Pharmacy Service, Shirasagi Hospital, Osaka 546-0002, Japan 3 Department of Medicine, Shirasagi Hospital, Osaka 546-0002, Japan These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 28 June 2013 / Revised: 1 August 2013 / Accepted: 6 August 2013 / Published: 19 August 2013
(This article belongs to the Special Issue Uremic Toxins)
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Abstract

In patients with end-stage renal disease, not only renal clearance but also hepatic clearance is known to be impaired. For instance, the concentration of erythromycin, a substrate of cytochrome P450 3A4 (CYP3A4), has been reported to be elevated in patients with end-stage renal disease. The purpose of this study is to elucidate the reason for the decrease in hepatic clearance in patients with end-stage renal disease. Deproteinized pooled sera were used to assess the effects of low-molecular-weight uremic toxins on CYP3A4 activity in human liver microsomes and human LS180 cells. Four uremic toxins (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, and 3-indoxyl sulfate) present at high concentrations in uremic serum were also studied. Simultaneous treatment of uremic serum (less than 10%) or uremic toxins did not affect testosterone 6β-hydroxylation in human liver microsomes. On the other hand, pretreatment of each serum activates CYP3A4 in LS180 cells, and the increased CYP3A4 activity in uremic serum-treated cells was smaller than normal serum-treated cells. In addition, CYP3A4 and CYP24A1 mRNA levels also increased in LS180 cells exposed to normal serum, and this effect was reduced in uremic serum-treated cells and in cells exposed to uremic serum added to normal serum. Furthermore, addition of 1,25-dihydroxyvitamin D to uremic serum partially restored the serum effect on CYP3A4 expression. The present study suggests that the decrease of 1,25-dihydroxyvitamin D and the accumulation of uremic toxins contributed to the decreased hepatic clearance of CYP3A4 substrates in patients with end-stage renal disease.
Keywords: CYP3A4; 1,25-dihydroxyvitamin D; uremic toxins; end-stage renal disease; vitamin D receptor (VDR) CYP3A4; 1,25-dihydroxyvitamin D; uremic toxins; end-stage renal disease; vitamin D receptor (VDR)
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Tsujimoto, M.; Nagano, Y.; Hosoda, S.; Shiraishi, A.; Miyoshi, A.; Hiraoka, S.; Furukubo, T.; Izumi, S.; Yamakawa, T.; Minegaki, T.; Nishiguchi, K. Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease. Toxins 2013, 5, 1475-1485.

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