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 cond itions at least 21 days. After confirming the CRF states, trimethadion e (TMO, 100 mg/kg, i.p.) was administered for evaluation of the hepati c drug metabolizing capacity; the ratio of dimethadione (DMO: the only metabolite of TMO) to TMO (DMO/TMO) in the serum and the dialysate fr om the blood microdialysis method were ascertained. The hepatic drug m etabolizing enzyme contents and activities were also determined. In th e CRF rats, the DMO/TMO ratios decreased significantly; total cytochro me P450 (CYP) contents, aminopyrine N-demethylase activity and delta-a minolevulinic 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 eva luated 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 alte ration of hepatic metabolism.