EFFECT OF POLOXAMER-407 ON THE ACTIVITY OF MICROSOMAL 3-HYDROXY-3-METHYLGLUTARYL-COA-REDUCTASE IN RATS

A single 300-mg i.p. injection of poloxamer 407 (P-407, also called Pl uronic F-127) in rats produces a marked hypercholesterolemia for a min imum of 96 h. The purpose of this investigation was to determine mecha nisms by which P-407 causes hypercholesterolemia. The enzyme targeted for investigation is the rate-limiting enzyme in cholesterolgenesis, 3 -hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Injection of P-407 in fasted rats resulted in a significant (p < 0.05) elevation i n plasma cholesterol (61.2 +/- 4.2 mg/dl) as soon as 1 h after injecti on compared with sham-injected controls (50.1 +/- 3.7 mg/dl). Plasma c holesterol (CHO) 24 h after injection of P-407 was 449 +/- 57 mg/dl, w ith the fastest rate of accumulation occurring from 1 to 12 h (approxi mate to 16.6 mg/dl/h). Over the concentration range of 0-5 mM, P-407 d id not appear significantly to affect the activity of HMG-CoA reductas e in vitro. However, the enzymatic activity assayed in microsomal frac tions isolated from the livers of P-407-injected rats reached a maximu m of 262 +/- 42.6 pmol mevalonate/min/mg similar to 15 h after injecti on, with a subsequent decline to control activity (93.1 +/- 8.7 pmol/m in/mg) at similar to 40 h after injection. At 48 h after injection of P-407, the activity of HMG-CoA reductase significantly (9 < 0.05) decr eased below control values with a mean activity of 9.4 +/- 1.2 pmol/mi n/mg. The CHO concentrations in hepatic tissue were significantly (p < 0.01) increased at 2 h (3.26 +/- 0.19 mg/g) and 4 h (3.75 +/- 0.38 mg /g) and significantly (p < .01) reduced at 15 h (1.56 +/- 0.19 mg/g) a fter injection of P-407 compared with tissue CHO concentrations determ ined in control animals (2.65 +/- 0.18 mg/g). However, the hepatic CHO content appeared to return to control values by 24 h (mean +/- SEM, 2 .61 +/- 0.08 mg/g) after injection. These data suggest that the activi ty of HMG-CoA reductase is regulated by some indirect mechanism(s) aft er injection of P-407 in rats.