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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
Received: 28 June 2013; in revised form: 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

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(8):1475-1485.

Chicago/Turabian Style

Tsujimoto, Masayuki; Nagano, Yui; Hosoda, Satomi; Shiraishi, Asuka; Miyoshi, Ayaka; Hiraoka, Shima; Furukubo, Taku; Izumi, Satoshi; Yamakawa, Tomoyuki; Minegaki, Tetsuya; Nishiguchi, Kohshi. 2013. "Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease." Toxins 5, no. 8: 1475-1485.



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