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

Toxins

Masayuki Tsujimoto³  Yui Nagano³  Satomi Hosoda³  Asuka Shiraishi³  Ayaka Miyoshi³  Shima Hiraoka³  Taku Furukubo²  Satoshi Izumi²  Tomoyuki Yamakawa¹  Tetsuya Minegaki³ 

[1] Department of Medicine, Shirasagi Hospital, Osaka 546-0002, Japan;Department of Pharmacy Service, Shirasagi Hospital, Osaka 546-0002, Japan;Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan

关键词: CYP3A4;    1;    25-dihydroxyvitamin D;    uremic toxins;    end-stage renal disease;    vitamin D receptor (VDR);   

DOI  :  10.3390/toxins5081475

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.