Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Simard, Émilie; Naud, Judith; Jl, Michaud; Leblond, François; Bonnardeaux, Alain; Guillemette, Chantal; Sim, Edith; Pichette, Vincent

doi:10.1681/asn.2007090974

Cited by 39 publications

(37 citation statements)

References 47 publications

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“…Mouse CYP1A2, CYP2C29, and CYP2E1 were detected using polyclonal goat anti-rat 1A1, 2C11, and 2E1 (Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan), respectively. CYP2D was detected by using a rabbit anti-human 2D (Oxford Biochemical Research Inc., Oxford, MI), CYP3A11 was detected by using a polyclonal goat anti-mouse 3A (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), and NAT2 was detected by using specific polyclonal rabbit anti-rat NAT2 as described previously (Stanley et al, 1996;Simard et al, 2008). ␤-Actin was detected by using a mouse anti-chicken ␤-actin (NeoMarkers, Fremont, CA).…”

Section: Methodsmentioning

confidence: 99%

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Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Dani¹,

Boisvert²,

Jl³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Drug metabolism could be altered in patients with chronic renal failure (CRF). In rats, this phenomenon is related to a decrease in liver cytochrome P450 (P450) and phase II enzymes, particularly N-acetyltransferase 2 (NAT2). This study attempted to determine the effects of CRF on liver P450 isoforms and NAT2 expressions by using a CRF mouse model. Two groups of mice were studied: CRF induced by 3/4 nephrectomy and control. Liver protein expression and mRNA levels of the major P450 isoforms involved in drug metabolism (CYP1A2, 2C29, 2D, 2E1, and 3A11) and NAT2 were measured by Western blot and realtime polymerase chain reaction (PCR), respectively. CYP3A activity was also assessed by the N-demethylation of erythromycin. Results showed a significant reduction in the protein expression of CYP1A2 (56%), 2C29 (31%), and 3A11 (37%) in CRF mice compared with control animals. Real-time PCR revealed a similar reduction in mRNA levels of CYP1A2, 2C29, and 3A11 (59, 56, and 37%, respectively), in CRF mice. There was no significant modification in protein expression and mRNA of CYP2D and 2E1. Compared with control animals, CRF mice displayed a 25% reduction in N-demethylation of erythromycin. For NAT2, protein expression decreased by 33% and mRNA levels decreased by 23%. In conclusion, this study demonstrates that protein expression of liver CYP1A2, CYP2C29, and CYP3A11 is down-regulated in CRF mice, secondary to reduced gene expression. Phase II enzymes are similarly affected by CRF. Our results will allow the use of knockout mice to determine the mechanism underlying CRF-induced down-regulation of liver drug-metabolizing enzymes.

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Section: Methodsmentioning

confidence: 99%

“…The mechanism underlying this decrease in P450 protein expression seems to be related to reduced gene expression (Leblond et al, 2000(Leblond et al, , 2001Nolin et al, 2008). Phase II enzymes, namely N-acetyltransferases (NATs), are equally down-regulated in CRF due to a decrease in gene expression (Simard et al, 2008).…”

mentioning

confidence: 99%

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Dani¹,

Boisvert²,

Jl³

et al. 2009

Drug Metab Dispos

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“…[123][124][125][126] Only a few studies have investigated the direct effect of uremic toxins on phase II enzymes. By using primary rat hepatocytes, Simard et al 127 showed that exposure of the cells to clinically relevant concentrations of parathyroid hormone resulted in a reduced gene and protein expression of N-acetyltransferase 2. Moreover, they observed a diminished N-acetylation of p-aminobenzoic acid in 5/6-nephrectomized rats.…”

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

“…Moreover, they observed a diminished N-acetylation of p-aminobenzoic acid in 5/6-nephrectomized rats. 127 In addition, Mutsaers et al 104 recently reported that more than 10 different uremic toxins, including indoxyl sulfate, kynurenic acid, and phenylacetic acid, diminished uridine diphosphate (UDP)-glucuronosyltransferase activity in ciPTEC, as shown by a reduction in glucuronidation of 7-hydroxycoumarin. Taken together, it is clear that uremic solutes can affect diverse intracellular targets and physiological processes, thereby hampering normal cellular functioning, illustrating the complex nature of uremic toxicity.…”

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

134

122

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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“…[27][28][29][30][31][32] More recently, we showed that this decrease in hepatic CYP450 may be explained by the presence of serum uremic factors that accumulate in CRF serum 33,34 and that parathyroid hormone (PTH) is a major mediator implicated in the downregulation of liver CYP450 and other liver drug-metabolizing enzymes. 35,36 Hence, an attractive hypothesis to explain the decreased synthesis of calcidiol in CRF is that uremic toxins and, more specific, elevated PTH could downregulate liver CYP450 isoforms implicated in the C-25-hydroxylation of vitamin D 3 ( Figure 1). Indirect evidence supporting such a hypothesis is that low serum levels of 25(OH)D 3 have also been reported in primary hyperparathyroidism and found to be corrected by parathyroidectomy (PTX).…”

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confidence: 99%

Reduced Hepatic Synthesis of Calcidiol in Uremia

Naud

Ouimet

et al. 2010

Journal of the American Society of Nephrology

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Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D 3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P Ͻ 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D 3 or 1␣-hydroxyvitamin D 3 , respectively, suggesting impaired C-25-hydroxylation of vitamin D 3 . Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms. ] deficiency has also been demonstrated in patients with stages 3 and 4 chronic kidney disease (CKD) and in patients who are on dialysis. [1][2][3][4][5][6][7][8] In fact, low serum 25(OH)D 3 is so intimately associated with CRF that in one study, only 29 and 17% of patients with stages 3 and 4 CKD, respectively, had sufficient levels [defined as a serum 25(OH)D 3 concentrations Ͼ75 nmol/L or 30 ng/ml]. 2 A more recent study showed a prevalence of calcidiol insufficiency and deficiency as high as 98% in predialysis patients with a mean GFR of 18.3 ml/min. 4 Prevalence of low serum 25(OH)D 3 was 78 and 89% in two large cohorts of hemodialysis patients 9,10 and 87% in a large cohort of peritoneal dialysis patients. 11 The metabolic consequences of calcidiol defi-

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Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure

Cited by 39 publications

References 47 publications

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

Down-Regulation of Liver Drug-Metabolizing Enzymes in a Murine Model of Chronic Renal Failure

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Reduced Hepatic Synthesis of Calcidiol in Uremia

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