MODULATIONS IN HEPATIC BRANCH-POINT ENZYMES INVOLVED IN ISOPRENOID BIOSYNTHESIS UPON DIETARY AND DRUG TREATMENTS OF RATS

Three branch-point enzymes of the mevalonate pathway, farnesyl pyropho sphate synthase, cis-prenyltransferase and squalene synthase were char acterized in rat hepatic cytosol, microsomes and peroxisomes isolated from rats after treatment with peroxisome proliferators, inducers of t he endoplasmic reticulum or modulators of lipid metabolism. Cholestyra mine and phenobarbital induced primarily the cytosolic farnesyl pyroph osphate synthase, whereas clofibrate and phthalates elevated the corre sponding peroxisomal activity. cis-Prenyltransferase activities in mic rosomes were induced 4-5-fold after clofibrate, phthalate and phenobar bital administration, but these same treatments affected the peroxisom al activity to only a limited extent. Squalene synthase activity in mi crosomes was completely abolished, but the peroxisomal activity was un affected after administration of cholesterol. On the other hand, clofi brate and phthalate induced only the microsomal activities. Mevinolin treatment greatly increased peroxisomal and cytosolic farnesyl pyropho sphate synthase activities, but not the mitochondrial activity, and th e cis-prenyltransferase activities were elevated in peroxisomes, but n ot in microsomes. These results demonstrate that the branch-point enzy mes in cholesterol and dolichol biosynthesis at various cellular locat ions are regulated differentially and that the capacities of peroxisom es and the endoplasmic reticulum to participate in the synthesis of po lyisoprenoid lipids is affected profoundly by treatment with different xenobiotics.