The effect of L-asparaginase on cholesterol biosynthesis.

Abstract

The liver from the Wistar rat was incubated either in the solution of 1 µCi acetate-1-14C or 0.1 µCi mevalonic acid-2-14C, and incorporations of radioactivity to phospholipid and cholesterol were estimated respectively. The incorporation of labeled acetate to cholesterol in the L-asparaginase-treated rat was significantly lower than that in the controls. However, there were no differences of the incorporation into the mevalonic acid between the study group and the controls. These results suggest that the inhibitory mechanism may exist between the steps of acetate and mevalonic acid.L-asparaginase; cholesterol biosynthesis; acute lymphocytic leukemiaSince the first report of successful L-asparaginase treatment of acute lymphocytic leukemia and malignant lymphoma (Oettgen et al. 1967) the clinical evaluation of this drug has been established. There, various side effects of the drug were also described. Among these, the decrease in serum lipids, especially cholesterol, is the most remarkable one . The serum protein decreases by L-asparaginase, which may be due to the suppression of protein biosynthesis (Bettigole et al. 1970). However, the cause of the change in cholesterol level was not clearly understood. The decrease in cholesterol may be derived from the disturbances of cholesterol synthesis or the acceleration of cholesterol catabolism and another possibility may be depending upon the decrement of lipoprotein, which works as a carrier of cholesterol. To know whether L-asparaginase influences the cholesterol biosynthesis, we carried out the following studies. MATERIALS AND METHODSMale Wistar rats weighing 150-200 g were used. L-Asparaginase (Kyowa Hakko Co.) was injected intravenously in a single dose of 2000 TI/kg. The rats were anesthetized with ether and the abdominal cavity was explored. Soon after exsanguination from the abdominal aorta, the liver was exstirpated and was sliced with a hand slicer. The liver slices were incubated in an oxygen filled flask with culture medium, which was put on a shaker at 37°C for 90 min. 0.25 g of the liver slices was weighed and incubated in 3 ml of phosphate buffer (pH 7.2) with 0.3 ml substrate (30 µmoles Na acetate+1 µCi acetate-1-14C or 0.1 µCi mevalonic acid-2-'4C). Filter paper dipped in 2 N NaOH was used for CO2 absorption, instead of using 1 M Hyamin in methanol solution which brought about