Inhibition of 3-Hydroxy-3-methylglutaryl Coenzyme A ReducÃ-ase Activity in Morris Hepatoma 7800 after Intravenous Injection of Mevalonic Acid1

The effect of i.v. injection of mevalonate on the activity of microsomal 3-hydroxy-3-methylglutaryl Conenzyme A reduc Ã-asewas studied in livers from non-tumor-bearing rats and in host liver and hepatomas from rats bearing transplantable Morris hepatoma 7800. We confirmed that a single bolus injection of 100 mg of mevalonate in non-tumor-bearing male rats caused a 90% inhibition of hepatic 3-hydroxy-3-methylglutaryl Coenzyme A reducÃ-ase activily wilhin 2 hr. In two experi ments, mevalonate injection caused a 50 to 60% reduction in enzyme activily of hepalomas but no significanl decline in the enzyme activity in host livers. Thirty min after injection of [14C]mevalonate in a similarly sized bolus, Ihe ralio of specific activities of cholesterol in liver:hepatoma:kidney:blood was 13: 5.6:0.5:1. Thus, bolh Ihe liver and hepaloma efficienlly utilized mevalonate for the synthesis of cholesterol. The precise cause of Ihe inhibition of enzyme aclivily in Ihe liver of non-lumorbearing rals and in the transplantable hepatomas is noi clear from this sludy. However, on Ihe basis of olher published reports, we suggesl lhal il resulted from the accumulalion of endogenous choleslerol in microsomal membranes. The aclivity of choleslerol 7a-hydroxylase, Ihe rale-conlrolling enzyme for bile acid synlhesis, was also sludied in the hepatoma, bul, in general, il did noi differ from lhal in Ihe hosl liver or conlrol liver.