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Alain Bonnardeaux

Publications and source records attributed to Alain Bonnardeaux.

7 recordsLinked to original sources
PubMed2006

Down-regulation of intestinal drug transporters in chronic renal failure in rats.

Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.

Animals↗
PubMed2006

Evidence that the mouse osteocalcin-related gene does not encode nephrocalcin.

BACKGROUND/AIMS: The osteocalcin-related gene (ORG) is a mouse-specific member of the osteocalcin gene cluster predicted to encode a gamma-carboxyglutamic acid-rich protein. ORG mRNA has been predicted to encode nephrocalcin and shown to be expressed in the kidney where it could serve as an important crystallization inhibitor. To determine whether ORG encodes mouse nephrocalcin, we investigated its in vivo and in vitro expression. METHODS: We expressed fluorescent fusion ORG proteins in kidney cell lines and generated transgenic mice expressing enhanced green fluorescent protein under the control of the ORG promoter. RESULTS: ORG mRNA was shown to be expressed in mouse kidneys and in a variety of other tissues. Fusion constructs transfected in opossum kidney cells demonstrated integrity of the open reading frame with the presence of a protein of the expected molecular weight. However, kidneys from transgenic mice carrying the enhanced green fluorescent protein gene under the control of the ORG promoter (5.8 kb fragment) demonstrated no expression of the transgene in kidneys or other tissues. CONCLUSION: We conclude that ORG, the third gene of the mouse osteocalcin gene cluster is silent and unlikely to play a major role in mouse renal physiology.

Animals↗
PubMed2005

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

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% (P<0.001) compared to control serum, while the levels of CYP2E1 were not modified. CYP3A and CYP1A activities were decreased by 51 and 59% (P<0.001), 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.

Adult↗
PubMed2005

Segregation of urine calcium excretion in families ascertained for nephrolithiasis: evidence for a major gene.

BACKGROUND: The quantitative genetics of urine calcium excretion has not been established. It is a trait of interest because hypercalciuria is commonly found in subjects with nephrolithiasis. The aim of this study was to model the segregation of this trait in a sample of French-Canadian families ascertained through a stone former. METHODS: Major gene, polygenic, and mixed models were fit to 24-hour urine calcium excretion from 567 individuals in 221 nuclear families, while simultaneously taking into account gender, age at examination, body mass index (BMI), and the use of thiazide drugs. The nuclear families were extracted from 154 pedigrees, some of which were four generations, with at least two siblings with a history of calcium stones. RESULTS: All the proposed genetic models fit the data significantly better than the null model. The most parsimonious model was the mixed codominant/polygenic model but it was statistically indistinguishable from the single-gene codominant model. In both of these models the heritability attributable to the major gene was estimated to be 0.58. CONCLUSION: Our results suggest that a major gene with a relatively large effect on variation in urine calcium excretion is segregating in French-Canadian families with stone formers. This implies that the power of quantitative trait segregation analysis of urine calcium excretion may be increased in these families, and results indicate that it should be feasible to genetically map the quantitative trait locus.

Adult↗
PubMed2002

Downregulation of intestinal cytochrome p450 in chronic renal failure.

Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.

Animals↗