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Vincent Pichette

Publications and source records attributed to Vincent Pichette.

18 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↗
PubMed2006

Use of a fluorescent substrate for the selective quantification of rat CYP3A in the liver and the intestine.

INTRODUCTION: Quantification of cytochrome P450 is a major issue in the development of new drugs. Different assays have been reported, but few are very selective for the 3A isoform or cytochrome P450. The benzyloxy-substituted lactone cyclooxygenase-2 inhibitor 3-[(3, 4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-one has recently been used successfully to probe isoform 3A of cytochrome P450 in the liver. However, its selectivity for the rat isoform remains to be established as well as its applicability in other tissue, such as the intestine. The purpose of this study was to ascertain the specificity of this substrate for the rat 3A isoform of cytochrome P450 using Supersomes and its application in non-hepatic tissue (e.g., intestine). METHODS: Specificity of the 3-[(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-methylsulfonyl)phenyl] furan-2(5H)-one for the isoform 3A of rat cytochrome P450 was established by using either isoform-specific inhibitory antibody or microsomes expressing only one cytochrome P450 isoform. Activity was assayed in rat liver and intestinal microsomal protein preparations. RESULTS: Experiments with inhibitory antibodies revealed that in liver and intestinal microsomes, more than 90% of the substrate metabolism was inhibited by antibodies against isoform 3A. Selectivity of the substrate for rat 3A isoform was further determined by testing the metabolic activity of various Supersomes preparations. DISCUSSION: In conclusion, our results validate the usefulness of 3-[(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-methylsulfonyl)phenyl] furan-2(5H)-one as a simple and specific substrate to study the activity of the isoform 3A of cytochrome P450 in the rat liver and intestine.

Animals↗
PubMed2006

Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes.

Neuropathic pain is one of the most inextricable problems encountered in clinics, because few facts are known about its etiology. Nerve injury often leads to allodynia and hyperalgesia, which are symptoms of neuropathic pain. The aim of this study was to understand some molecular and electrophysiological mechanisms of neuropathic pain after chronic constriction of the saphenous nerve (CCS) in mice. After surgery, CCS mice displayed significant allodynia and hyperalgesia, which were sensitive to acute systemic injection of morphine (4 mg/kg), gabapentin (50 mg/kg), amitriptyline (10 mg/kg), and the cannabinoid agonist WIN 55,212-2 (5 mg/kg). These behavioral changes were accompanied after surgery by an increase of c-Fos expression and by an overexpression of mu-opioid and cannabinoid CB1 and CB2 receptors in the spinal cord and the dorsal hind paw skin. In combination with the skin-nerve preparation, this model showed a decrease in functional receptive fields downstream to the injury and the apparition of A-fiber ectopic discharges. In conclusion, CCS injury induced behavioral, molecular, and electrophysiological rearrangements that might help us in better understanding the peripheral mechanisms of neuropathic pain. This model takes advantage of the possible use in the future of genetically modified mice and of an exclusively sensory nerve for a comprehensive study of peripheral mechanisms of neuropathic pain.

Action Potentials↗
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

Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis.

BACKGROUND: Secondary hyperparathyroidism develops early in patients with chronic kidney disease (CKD). Clinical guidelines from the National Kidney Foundation-Kidney/Disease Outcomes Quality Initiative emphasize the need to control parathyroid hormone (PTH), calcium, and phosphorus levels in patients with CKD not receiving dialysis to reduce poor outcomes. This phase 2 study evaluated the effects of the oral calcimimetic cinacalcet hydrochloride in patients with CKD not on dialysis therapy. METHODS: A randomized, double-blind, placebo-controlled, 18-week study enrolled adults with an estimated glomerular filtration rate of 15 to 50 mL/min/1.73 m2 (0.25 to 0.83 mL/s/1.73 m2) and an intact PTH (iPTH) level greater than 130 pg/mL (ng/L). Cinacalcet (or placebo) was titrated from 30 to 180 mg once daily to obtain a 30% or greater reduction in iPTH levels from baseline. RESULTS: Baseline mean iPTH levels were 243 pg/mL (ng/L) in the cinacalcet group (n = 27) and 236 pg/mL (ng/L) in the control group (n = 27). At baseline, 28% of subjects were being administered vitamin D sterols and 43% were being administered phosphate binders or calcium supplements. The addition of cinacalcet significantly decreased iPTH concentrations compared with controls during the efficacy-assessment phase: 56% versus 19% of subjects achieved a 30% or greater reduction in iPTH levels (P = 0.006), and mean iPTH levels decreased by 32% in the cinacalcet group, but increased by 6% in the control group (P < 0.001). Mean serum calcium and phosphorus levels remained within normal range throughout the study. Cinacalcet generally was well tolerated; the most frequent adverse events were gastrointestinal. CONCLUSION: This preliminary study provides evidence that cinacalcet is efficacious for the treatment of secondary hyperparathyroidism in subjects with CKD not receiving dialysis.

Calcium↗
PubMed2005

Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.

BACKGROUND: This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data. METHODS: One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months. RESULTS: One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002). CONCLUSION: This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Adult↗
PubMed2004

Darbepoetin alfa effectively treats anemia in patients with chronic kidney disease with de novo every-other-week administration.

AIM: This multicenter, open-label study determined safety and efficacy of once-every-other-week administration of darbepoetin alfa for anemia of chronic kidney disease in erythropoietin-naive patients not on dialysis. METHODS: Participants with hemoglobin levels <11.0 g/dl at baseline were administered darbepoetin alfa at an initial dosage of 0.75 microg/kg once every other week. The dose was titrated to achieve and maintain a hemoglobin response, defined as a hemoglobin range of between 11.0 and 13.0 g/dl for up to 24 weeks. The primary end point was the dose of darbepoetin alfa at initial hemoglobin response. RESULTS: Six hundred and eight patients were enrolled, and 463 completed the study; 95% (95% confidence interval: 0.93, 0.97) of the patients who completed treatment achieved a hemoglobin response. The mean darbepoetin alfa dose at the time of response was 63.5 +/- (SD) 16.9 microg, and the mean time to hemoglobin response was 5.7 +/- (SD) 4.5 weeks. Oral iron therapy was administered to 60% and intravenous iron to 16% of the participants. Darbepoetin alfa was well tolerated, and adverse events were consistent with those expected in patients with chronic kidney disease. CONCLUSION: Darbepoetin alfa administered once every other week is effective and safe for achieving and maintaining target hemoglobin levels in anemic patients with chronic kidney disease.

Adult↗
PubMed2003

Interleukin-1beta, interleukin-6, tumour necrosis factor-alpha and interferon-gamma released by a viral infection and an aseptic inflammation reduce CYP1A1, 1A2 and 3A6 expression in rabbit hepatocytes.

Inflammation reduces activity and expression of hepatic cytochrome P450 (P450) and therefore diminishes drug biotransformation. This study aimed to identify the serum mediators triggered by a viral infection and an aseptic inflammation that downregulate P450 isoforms. Incubation of hepatocytes with serum from rabbits with a turpentine-induced inflammation or humans with a viral infection decreased the amount of cytochrome 1A1 (CYP1A1), 1A2 and 3A6 mRNA and apoproteins. By serum fractionation and immuno-neutralization, we showed that in the aseptic inflammation, interleukin-6 and, to a lesser degree, interleukin-1beta are involved in the downregulation of all three isoforms. In serum from humans with a viral infection, interleukin-1beta, interleukin-6, interferon-gamma and tumour necrosis factor-alpha contribute to the downregulation of P450 isoforms. CYP1A1 and 1A2 are regulated by serum mediators at the transcriptional level, while the expression of CYP3A6 appears to be under the control of pre- and posttranscriptional mechanisms.

Animals↗
PubMed2003

Atheroembolic renal failure requiring dialysis: potential for renal recovery? A review of 43 cases.

AIMS: Our objectives were to review the characteristics of patients who developed atheroembolic renal disease requiring dialysis as well as their renal function recovery and survival rates. METHODS: All cases of atheroembolic disease with renal failure severe enough to require dialysis were reviewed from January 1984 to December 2000 in two centers. The diagnosis of atheroemboli was based on clinical presentation and/or biopsy. Acute renal failure was defined as a serum creatinine >200 micromol/l if normal at baseline or doubling from baseline if chronic renal failure, whereas renal function recovery was the ability to discontinue renal replacement therapy for >or=3 months. RESULTS: Forty-three cases were identified (37 males and 6 females; mean age 67 +/- 5 years); the average time to acute renal failure and to diagnosis was similar at 36 days. The majority of patients had at least one precipitating factor identified (58% coronary angiography, 26% angiography, 16% vascular surgery, 2% anticoagulation); 1 had a spontaneous presentation whereas 7 had more than one factor. More than 90% had underlying hypertension and chronic renal dysfunction with a baseline creatinine of 195 +/- 81 micromol/l, approximately 80% had coronary artery disease, 80% were smokers, 60% had a history of abdominal aorta aneurysm, >50% presented with intermittent claudication, and 56% were anticoagulated at the time of the event. Most patients were nonoliguric (80%), had increased hypertension (71%), blue toes (67%), livedo reticularis (52%), whereas abdominal pain and central nervous system symptoms were present in 33 and 7% of the cases, respectively. Eosinophilia was found in 88%, while hypocomplementemia was present in less than 15%. When compared to the 12 patients with recovery of renal function (after a mean delay of 409 +/- 336 days), the 31 patients who did not recover function presented with more severe intermittent claudication and underlying chronic renal dysfunction (p < 0.05). Indeed, the only variable found to unfavorably influence renal function recovery was the presence of intermittent claudication. Patients were mainly treated by intermittent hemodialysis except for 5 (2 on CRRT and 3 on peritoneal dialysis). Renal function recovery was associated with a higher chance of survival; 33% of patients died in the first year after diagnosis. CONCLUSION: Atheroembolic renal disease carries a high mortality rate reflective of the extensive cardiovascular disease of affected patients; nevertheless, the potential for renal function recovery appears greater than for other vascular causes of renal failure.

Acute Kidney Injury↗
PubMed2003

Drug metabolism in chronic renal failure.

Pharmacokinetic studies conducted in patients with CRF demonstrate that the nonrenal clearance of multiple drugs is reduced. Although the mechanism by which this occurs is unclear, several studies have shown that CRF affects the metabolism of drugs by inhibiting key enzymatic systems in the liver, intestine and kidney. The down-regulation of selected isoforms of the hepatic cytochrome P450 (CYP450) has been reported secondary to a decrease in gene expression. This is associated with major reductions in metabolism of drugs mediated by CYP450. The main hypothesis to explain the decrease in liver CYP450 activity in CRF appears to be the accumulation of circulating factors which can modulate CYP450 activity. Liver phase II metabolic reactions are also reduced in CRF. On the other hand, intestinal drug disposition is affected in CRF. Increased bioavailability of several drugs has been reported in CRF, reflecting decrease in either intestinal first-pass metabolism or extrusion of drugs (mediated by P-glycoprotein). Indeed, intestinal CYP450 is also down-regulated secondary to reduced gene expression, whereas, decreased intestinal P-glycoprotein activity has been described. Finally, although the kidneys play a major role in the excretion of drugs, it has the capacity to metabolize endogenous and exogenous compounds. CRF will lead to a decrease in the ability of the kidney to metabolize drugs, but the repercussions on the systemic clearance of drugs is still poorly defined, except for selected xenobiotics. In conclusion, reduced drug metabolism should be taken into account when evaluating the pharmacokinetics of drugs in patients with CRF.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6 involves serum mediators.

1. Acute moderate hypoxia modifies the catalytic activity and expression of certain isoenzymes of hepatic cytochrome P450 (P450). The aim of this study was to document whether hypoxia affects hepatic P450 directly or through the release of serum mediators. 2. Rabbits were subjected to a FiO(2) of 8% for 48 h, sacrificed, and serum and hepatocytes were isolated; hepatocytes from control and rabbits with hypoxia were incubated with serum from control and hypoxic rabbits for 4 and 24 h, and total P450 content, CYP1A1, 1A2 and 3A6 activities and expressions were assessed. Sera were fractionated by size exclusion chromatography and fractions tested for their ability to modify activity and amount of P450, and serum mediators were identified through neutralization experiments. 3. Total serum and fractions with proteins of 15-23 and 65-94 kDa of M(r) reduced P450 content and expression of CYP1A1, 1A2 and 3A6, as well as CYP1A1, 1A2 and 3A6 mRNA. Total serum and the fraction with 32-44 kDa proteins increased CYP3A6 activity and protein and mRNA. The serum mediators implicated in the decrease in activity and expression of CYP1A1, 1A2 and 3A6 were interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta) and IL-2. Erythropoietin (Epo) was partly responsible for the increase in P450 content and CYP3A6 expression. 4. In conclusion, acute moderate hypoxia diminishes the activity and expression of CYP1A1, 1A2 and CYP1A1, 1A2 mRNA, and increases CYP3A6 protein, activity and CYP3A6 mRNA. Several mechanisms contribute to these changes in P450, among them the release of cytokines acting as serum mediators.

Animals↗
PubMed2002

Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators.

1. Chronic renal failure (CRF) is associated with a decrease in liver cytochrome p450 (p450). The mechanism remains poorly understood. The present study aimed to investigate the effects of the serum of rats with CRF on liver p450. 2. Normal rat hepatocytes were incubated for 24 h with serum (concentration of 10%) from rats with CRF and from control animals in order to measure (1). total p450 level, (2). protein expression and mRNA levels of major p450 isoforms, and (3). some of their specific metabolic activities (N-demethylation of erythromycin). Time-course experiments (incubation time from 12 to 48 h) and dose-response curves (concentration of serum ranging from 1 to 30%) have been conducted. 3. In normal hepatocytes incubated for 24 h with serum (concentration of 10%) from rats with CRF, total p450 level, protein expression and mRNA levels of several p450 isoforms (CYP2C6, 2C11, 3A1 and 3A2) were decreased by more than 35% (P<0.001) compared to serum from control animals. The protein expression as well as the mRNA levels of CYP2D were similar in hepatocytes incubated with serum from either control or CRF rats. The N-demethylation of erythromycin was decreased by more than 35% (P<0.001) in hepatocytes incubated with serum from rats with CRF. The inhibitory effect of serum from rats with CRF tended to peak at 48 h of incubation and was maximum at a concentration of 20%. 4. In conclusion, uremic serum contains mediator(s) that down-regulate the cytochrome p450 of normal hepatocytes secondary to reduced gene expression.

Animals↗
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↗
PubMed2001

Downregulation of hepatic cytochrome P450 in chronic renal failure.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats. Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.

Animals↗