1997 Volume 9 Issue 1 Pages 67-75
Effects of adenine-induced chronic renal failure (CRF) on hepatic microsomal oxidative drug-metabolizing enzymes and heme-metabolizing enzymes were examined. Male Sprague-Dawley rats, 5 weeks old, were used in this study. An adenine-induced CRF model was produced in rats by feeding a diet containing adenine (0.5 w/w% in regular chow) for 5 weeks under regular conditions. The state of CRF was confirmed by changes in serum levels of blood urea nitrogen (BUN) and creatinine, after which activities and contents of hepatic microsomal drug-metabolizing enzymes were determined. In CRF rats, significant and successive increases in serum BUN and creatinine were observed. Morphologic changes were observed in the kidneys of CRF rats: the volume increased approximately three fold and the color changed to ivory white. Significant decreases in the demethylation of erythromycin, which is mainly metabolized by cytochrome P450 3A2 (CYP3A2), and in the activity of mitochondrial delta-aminolevulinic acid synthetase (ALAS) were observed (p<0.001 and p<0.05 ), respectively) . Aminopyrine N-demethylase activity was slightly decreased. On the other hand, cytochrome b5 contents and aniline hydroxylase activity were significantly increased in CRF rats (p<0.01 and 0.05, respectively) . The changes in erythromycin N-demethylase and ALAS activities were negatively correlated with serum BUN and creatinine concentrations. In conclusion, the hepatic microsomal drug-metabolizing enzyme system was affected by conditions of CRF. The adenine-induced CRF model will be a useful tool for estimating changes in drug metabolism in CRF.
