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.

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

“…Studies of ESRD have shown that CMPF indirectly inhibits the activity of cytochrome P450 3A4 (CYP3A4). 31,32 An important drug-metabolizing enzyme, CYP3A4 activity is altered in patients afflicted with ESRD through its association with the VDR, with CYP3A4 expression being controlled by both VDR and the pregnane X receptor (PXR) which are induced by 1,25(OH)D. 31,34 In cases of ESRD, increases in uremic toxins of 10-fold or more 32 limit the ability of VDR to bind to vitamin D response elements and inhibit CYP3A4 activity. 31 CYP3A4…”

“…A furan fatty acid metabolite, CMPF has been linked with numerous diseases, including type-2 diabetes (T2D), end-stage renal disease (ESRD) and gestational diabetes mellitus (GDM). [29][30][31] In its association with ESRD and chronic renal failure, CMPF is characterized as a uremic toxin 31,32 that is created when furan fatty acids are incorporated into phospholipids and cholesterol esters, catabolized and excreted in the urine 33 possibly altering renal vitamin D metabolism. Studies of ESRD have shown that CMPF indirectly inhibits the activity of cytochrome P450 3A4 (CYP3A4).…”

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Hippuric acid, indoxyl sulfate, CMPF and p-cresol all individually inhibit CYP3A4 mediated metabolism of testosterone in human microsomes [47]. Additionally, a combination of hippuric acid, CMPF, indoxyl sulfate and indole-3-acetic acid also perpetrate a significant decrease of CYP3A4 mRNA expression [53]. Indoxyl sulfate also inhibits CYP3A4 activity in human hepatocytes and microsomes, animal models and potentially in kidney disease patients [54–56].…”

“…Indoxyl sulfate plasma concentrations are inversely related to CYP3A4 activity measured by endogenous 4β-hydroxycholesterol formation in stable renal transplant patients [57]. Conversely, some reports suggest that indoxyl sulfate or other microbial toxins have no interactions with CYP3A4 activity or expression [53,58]. The reason for discordant findings between studies is unclear, but might be due to differences in experimental procedures.…”

Hepato‐splanchnic circulatory stress: An important effect of hemodialysis

“…Hepatic metabolic function has been more widely shown to be affected by individual uremic toxins. The commonly‐studied toxin, indoxyl sulfate, has been repeatedly shown to affect hepatic synthetic production and elements of drug metabolism . p‐Cresol has also been shown to affect drug metabolism within the liver, as well as influencing hepatic uptake of other toxic substances such as aluminium .…”