title: 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: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. tsujimt@mb.kyoto-phu.ac.jp
authors: Masayuki
authors: M
authors: Tsujimoto
authors: Yui
authors: Y
authors: Nagano
authors: Satomi
authors: S
authors: Hosoda
authors: Asuka
authors: A
authors: Shiraishi
authors: Ayaka
authors: A
authors: Miyoshi
authors: Shima
authors: S
authors: Hiraoka
authors: Taku
authors: T
authors: Furukubo
authors: Satoshi
authors: S
authors: Izumi
authors: Tomoyuki
authors: T
authors: Yamakawa
authors: Tetsuya
authors: T
authors: Minegaki
authors: Kohshi
authors: K
authors: Nishiguchi
mesh_terms: D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004917:Erythromycin / Q000627:therapeutic use; D005663:Furans / Q000097:blood; D006626:Hippurates / Q000097:blood; D006801:Humans; D007200:Indican / Q000097:blood; D007210:Indoleacetic Acids / Q000097:blood; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000077297:Pregnane X Receptor; D011422:Propionates / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014118:Toxins, Biological / Q000097:blood*; D014807:Vitamin D / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C468134:3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; D005663:Furans; D006626:Hippurates; D007210:Indoleacetic Acids; D000077297:Pregnane X Receptor; D011422:Propionates; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014118:Toxins, Biological; D014807:Vitamin D; D004917:Erythromycin; C030737:indoleacetic acid; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D007200:Indican; C030514:hippuric acid
references: Biochemistry. 2010 Jan 19;49(2):393-400
references: 20000589
references: Clin Pharmacol Ther. 2008 Dec;84(6):704-9
references: 18509328
references: Drug Metab Pharmacokinet. 2004 Aug;19(4):280-9
references: 15499196
references: Biochem Biophys Res Commun. 2010 Mar 19;393(4):688-93
references: 20171174
references: Circulation. 1982 Dec;66(6):1277-80
references: 7139903
references: Clin Pharmacol Ther. 2010 Apr;87(4):465-72
references: 20090676
references: J Biol Chem. 2010 May 14;285(20):15599-15610
references: 20236932
references: Kidney Int. 2007 Jan;71(1):31-8
references: 17091124
references: J Biol Chem. 2001 May 4;276(18):14581-7
references: 11297522
references: J Am Soc Nephrol. 2009 Oct;20(10):2269-76
references: 19696225
references: J Pharm Sci. 2011 Sep;100(9):3831-42
references: 21618544
references: J Am Soc Nephrol. 2001 Feb;12(2):326-332
references: 11158222
references: J Biol Chem. 2002 Jul 12;277(28):25125-32
references: 11991950
references: J Pharmacol Sci. 2008 Oct;108(2):157-63
references: 18845914
references: Ther Drug Monit. 2008 Oct;30(5):576-82
references: 18708994
references: J Pharm Pharmacol. 2010 Jan;62(1):133-8
references: 20723009
references: Nephrol Dial Transplant. 2003 May;18(5):967-76
references: 12686673
references: Clin Pharmacol Ther. 2006 Dec;80(6):597-606
references: 17178261
references: Drug Metab Dispos. 2004 Nov;32(11):1239-46
references: 15286055
references: J Clin Invest. 1995 Jul;96(1):50-9
references: 7615822