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Downregulation of intestinal cytochrome p450 in chronic renal failure
Francois A Leblond1, Martin Petrucci, Pierre Dubé
1Nephrology Service and Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculty of Medicine, Université de Montréal, Québec, Canada.
Abstract:
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.
Insights
Chronic renal failure (CRF) reduces intestinal drug metabolism by decreasing cytochrome P450 (CYP) enzyme activity, primarily CYP1A1 and CYP3A2, due to lower gene expression in rats.
Area of Science:
- Pharmacology
- Nephrology
- Biochemistry
Background:
- Chronic renal failure (CRF) is linked to impaired intestinal drug metabolism.
- Reduced cytochrome P450 (CYP) levels are hypothesized to be a contributing factor.
- Understanding these mechanisms is crucial for managing drug therapy in CRF patients.
Purpose of the Study:
- To investigate the impact of CRF on intestinal CYP levels and activity in a rat model.
- To identify specific CYP isoforms affected by CRF.
- To explore the relationship between CRF and gene expression of intestinal CYPs.
Main Methods:
- CRF was induced in rats via 5/6 nephrectomy; controls were pair-fed.
- Intestinal microsomes were analyzed for total CYP activity, protein, and mRNA expression.
- Enzyme activities of CYP1A and CYP3A were assessed using specific probe substrates.
Main Results:
- CRF rats showed a 77% reduction in creatinine clearance and a 32% decrease in total intestinal CYP activity.
- Protein and mRNA levels of CYP1A1 and CYP3A2 were significantly reduced in CRF rats (>40%).
- Specific activities for CYP1A and CYP3A probes were decreased by 25% in CRF.
Conclusions:
- CRF in rats is associated with significantly reduced intestinal CYP activity, mainly affecting CYP1A1 and CYP3A2.
- This reduction is primarily due to decreased gene expression of these CYP isoforms.
- Despite reduced levels, intestinal CYPs in CRF rats retained inducibility by dexamethasone.