Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Abstract

1. ML‐236A and ML‐236B, potent inhibitors of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase, were readily absorbed into the liver, the major site of cholesterogenesis, after oral administration in mice; peak concentration of these inhibitors in the liver, which were attained within 60 min after administration, were 4% of the dose for ML‐236A and 10% for ML‐236B, respectively.2. ML‐236B reduced sterol synthesis from both [14C]acetate and [14C]octanoate in rat liver slices to 50% of control at a concentration of 0.05 μg/ml (0.12 μM) but not that from [14C]mevalonate at higher concentrations up to 1.25 μg/ml. Inhibition of sterol synthesis was also observed in liver slices obtained from rats which had previously received this compound.3. ML‐236B was also inhibitory in vivo to cholesterol synthesis in various tissues of rats in which [14C]acetate was intraperitoneally injected to the animals and labeled digitonin‐precipitable sterols synthesized were isolated and determined. Sterol synthesis in the liver was far more strongly inhibited (over 90 % at 4h after oral administration of 50 mg/kg of ML‐236B) than that in other organs tested including kidney, lung, adrenal, spleen, and testis.4. These findings strongly suggest that hypocholesterolemic activity of ML‐236A and ML‐236B is owing largely to specific inhibition of hepatic cholesterol synthesis.