Effects of decreased vitamin D and accumulated uremic toxin on human CYP3A4 activity in patients with end-stage renal disease.

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.

• Authors: Masayuki Tsujimoto, Yui Nagano, Satomi Hosoda, Asuka Shiraishi, Ayaka Miyoshi, Shima Hiraoka, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki, Kohshi Nishiguchi
• Journal: Toxins (Toxins (Basel)) Vol. 5 Issue 8 Pg. 1475-85 (Aug 19 2013) ISSN: 2072-6651 [Electronic] Switzerland
• PMID: 23965431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid
• Furans
• Hippurates
• Indoleacetic Acids
• Pregnane X Receptor
• Propionates
• RNA, Messenger
• Receptors, Calcitriol
• Receptors, Steroid
• Toxins, Biological
• Vitamin D
• Erythromycin
• indoleacetic acid
• Steroid Hydroxylases
• Cytochrome P-450 CYP3A
• steroid hormone 6-beta-hydroxylase
• CYP3A4 protein, human
• CYP24A1 protein, human
• Vitamin D3 24-Hydroxylase
• Indican
• hippuric acid

Topics

• Cell Line, Tumor
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Erythromycin (therapeutic use)
• Furans (blood)
• Hippurates (blood)
• Humans
• Indican (blood)
• Indoleacetic Acids (blood)
• Kidney Failure, Chronic (drug therapy, physiopathology)
• Liver (drug effects, metabolism)
• Microsomes, Liver (drug effects, metabolism)
• Pregnane X Receptor
• Propionates (blood)
• RNA, Messenger (genetics, metabolism)
• Receptors, Calcitriol (genetics, metabolism)
• Receptors, Steroid (genetics, metabolism)
• Steroid Hydroxylases (genetics, metabolism)
• Toxins, Biological (blood)
• Vitamin D (blood)
• Vitamin D3 24-Hydroxylase