Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450

Abstract

1 In humans, chronic renal failure (CRF) is associated with decreased hepatic drug metabolism, particularly that mediated by the cytochrome P450 (P450). The mechanisms remain poorly understood. The present study aimed to investigate the effects of the serum of patients with CRF on liver P450, and to evaluate whether renal replacement therapies (dialysis or transplantation) impede the inhibition of CRF serum on P450. 2 Rat hepatocytes were incubated for 24 h with serum from patients with severe CRF and from controls to measure (1) P450 level, (2) protein expression and mRNA levels of P450 isoforms and (3) metabolic activities of CYP3A and CYP1A. Similar experiments were performed with serum of patients once on chronic hemodialysis and after kidney transplantation. 3 In rat hepatocytes incubated for 24 h with serum from patients with CRF, P450 level and protein expression, as well as mRNA levels of P450 isoforms (CYP1A2, 2C6, 2C11, 2D1/2D2, 3A2 and 4A1/ 4A3), were decreased by more than 45% (Po0.001) compared to control serum, while the levels of CYP2E1 were not modified. CYP3A and CYP1A activities were decreased by 51 and 59% (Po0.001), respectively. The inhibitory effect of serum obtained from patients before first dialysis was similar after 1 or 6 months on chronic hemodialysis but was lost after successful kidney transplantation. In CRF serum, the fraction containing proteins between 10 and 15 kDa decreases P450. 4 Human uremic serum contains mediator(s) that decreases rat hepatic P450 activity and expression secondary to reduced gene expression. The inhibitory effect of serum persists even after initiation of dialysis, but disappears after normalization of renal function following kidney transplantation.

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

“…This decrease in protein expression of P450 isoforms was secondary to reduced gene expression (11). Similar results have been shown with serum of patients with severe CRF (12). The next step was to find which factor in the uremic blood downregulates P450 in CRF.…”

Phase I Trial of Rosiglitazone in FSGS

“…GFR was an important contributor to AUC 0 to ϱ and AUC 0 to 12 . In patients with diminished GFR, decreased hepatic metabolism secondary to CKD itself (17) or the effect of CKD on the accumulation of endogenous substrates (18,19), may result in an increased AUC of rosiglitazone. In subjects with both decreased albumin and decreased GFR, the AUC lowering effect of hypoalbuminemia may be balanced by an increased AUC effect of a reduced GFR.…”

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

“…This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.…”

“…Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6,10,11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated with human uremic serum (14). More directly relevant to the effects of chronic kidney disease (CKD) on hepatic transport were studies demonstrating that 5/6N induced downregulation of the uptake transporters Oatp1a1, Oatp1a4, and Oatp1b2 in rats (7,15).…”