Oxidative drug metabolism in liver microsomes from uremic rats.

Oxidative drug metabolism in liver microsomes from uremic rats. Uremia was achieved by subtotal nephrectomy in 50 to 70 day old male rats weighing 252.0± 20.1 g. Nephrectomized rats and sham-operated controls were sacrificed six days later. After liver microsomes had been isolated, microsomal cytochrome P-450 and cytochrome b5 content as well as microsomal specific activity for N-demethylation of aminopyrine, O-demethylation of p-nitroanisole and p-hydroxylation of acetanilide were measured. Serum urea concentration rose to 370.0± 80.0 mg/100 ml. The serum creatinine rose to 4.8±1.2 mgJlOO ml. In sham-operated controls serum urea and creatinine concentrations were approximately 50 and 0.6 mg/100 ml, respectively. Uremic rats, in contrast to sham-operated controls, lost about 25% of their initial body wt. In uremic rats and in sham-operated controls with caloric deficiency there was a significant decrease of total microsomal protein to 51 % of the value measured in sham-operated controls fed ad libitum. Absolute and relative liver wet wt decreased more in caloric deficient controls than in uremic rats, whereas microsomal protein content per g liver was lower in uremic rats. In comparison with sham-operated controls, there was a pronounced decrease in the specific activity of liver microsomes from uremic rats for the demethylation of aminopyrine and p-nitroanisole and for the p-hydroxylation of acetanilide. The microsomal cytochrome P-450 content was also significantly diminished, whereas the microsomal cytochrome b5 content was not influenced, but there was stimulation of the O-demethylation of p-nitroanisole to 125.1 % when compared to controls fed ad libitum. Four intraperitoneal injections of 6 mg 6-aminolevulinic acid/kg body given to uremic rats normalized the cytochrome P-450 content and significantly stimulated the specific activity for demethylation of p-nitroanisole, whereas demethylation of aminopyrine, p-hydroxylation of acetanilide and cytochrome b5 content were not altered. In sham-operated controls none of the measured parameters were influenced by 6-aminolevulinic acid pretreatment. It is assumed that the reduction of cytochrome P-450 content in liver microsomes from uremic rats is caused by a deficiency of -aminolevulinic acid which leads to disturbances in cytochrome synthesis. The observed decrease in the ability of liver microsomes from uremic rats to metabolize aminopyrine, p-nitroanisole and acetanilide is not merely due to reduced cytochrome P-450 content.