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Changes of hepatic microsomal oxidative drug metabolizing enzymes in chronic renal failure (CRF) rats by partial
N Uchida1, N Kurata, K Shimada
1Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
Abstract:
Male SD rats, 7-weeks-old, were used to investigate the changes in the hepatic drug metabolizing system of chronic renal failure (CRF) model rats. Partial nephrectomy (5/6) was performed in a two-stage surgical procedure. After nephrectomy, the rats were housed under regular conditions at least 21 days. After confirming the CRF states, trimethadione (TMO, 100 mg/kg, i.p.) was administered for evaluation of the hepatic drug metabolizing capacity; the ratio of dimethadione (DMO: the only metabolite of TMO) to TMO (DMO/TMO) in the serum and the dialysate from the blood microdialysis method were ascertained. The hepatic drug metabolizing enzyme contents and activities were also determined. In the CRF rats, the DMO/TMO ratios decreased significantly; total cytochrome P450 (CYP) contents, aminopyrine N-demethylase activity and delta-aminolevulinic acid synthetase activity also decreased significantly in the CRF rats. The extent of the alterations of these enzyme contents and activities correlated well with the severity of the CRF states evaluated by the serum blood urea nitrogen and creatinine concentrations. With Western blot analysis, the levels of CYP2C6, CYP2C11 and CYP3A2 decreased considerably in the CRF rats. These results suggest that CRF states induce not only a reduction of renal function but also an alteration of hepatic metabolism.
Insights
Chronic renal failure (CRF) in rats significantly impairs hepatic drug metabolism, reducing key enzyme activities and altering drug processing. These changes correlate with kidney function decline, impacting overall liver function.
Area of Science:
- Pharmacology
- Nephrology
- Hepatology
Background:
- Chronic renal failure (CRF) affects multiple organ systems.
- Hepatic drug metabolism is crucial for xenobiotic clearance.
- The impact of CRF on liver drug-metabolizing enzymes requires further elucidation.
Purpose of the Study:
- To investigate the functional and compositional changes in the hepatic drug metabolizing system of CRF model rats.
- To assess the correlation between CRF severity and alterations in drug metabolism.
Main Methods:
- A 5/6 partial nephrectomy model was used to induce CRF in male Sprague-Dawley rats.
- Trimethadione (TMO) was administered to evaluate hepatic drug metabolizing capacity via serum and microdialysis.
- Hepatic drug-metabolizing enzyme content and activity, including cytochrome P450 (CYP) levels, were determined using biochemical assays and Western blot analysis.
Main Results:
- CRF rats exhibited significantly decreased DMO/TMO ratios, indicating reduced hepatic drug metabolism.
- Total CYP content, aminopyrine N-demethylase, and delta-aminolevulinic acid synthetase activities were significantly reduced in CRF rats.
- Levels of specific CYP isoforms (CYP2C6, CYP2C11, CYP3A2) were considerably decreased, correlating with serum creatinine and blood urea nitrogen concentrations.
Conclusions:
- CRF significantly alters hepatic drug metabolism, leading to reduced enzyme activity and expression.
- The severity of CRF correlates with the extent of hepatic metabolic dysfunction.
- CRF impacts not only renal function but also the liver's capacity to metabolize drugs.