Changes of hepatic microsomal oxidative drug metabolizing enzymes in chronic renal failure (CRF) rats by partial nephrectomy.
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.
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
N
N
Uchida
N
N
Kurata
K
K
Shimada
Y
Y
Nishimura
K
K
Yasuda
M
M
Hashimoto
E
E
Uchida
H
H
Yasuhara
D000818:Animals; D015153:Blotting, Western; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D008099:Liver / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009392:Nephrectomy; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004364:Pharmaceutical Preparations; D003346:Corticotropin-Releasing Hormone; D003577:Cytochrome P-450 Enzyme System