Enzymes of the mevalonate pathway in rat liver nodules induced by 2-acetylaminofluorene treatment

Certain enzymes of the mevalonate pathway have been investigatedin persistent liver nodules induced in the rat by 2-acetylaminofluorene.In these nodules the dolichol level was increased 5-fold, theubiquinone-9 content elevated 6-fold and the amount of cholesterolunchanged. Microsomal ß-hydroxy-ß-methylglutaryl-coenzymeA reductase activity was greatly increased compared to controlliver tissue, which was also the case for the cytosolic farnesylpyrophosphate synthase. A significant elevation of all-trans-geranylgeranylpyrophosphate synthase activity in the cytosol was also observed.The branch-point enzyme of microsomal dolichol synthesis, i.e.cis-prenyltransferase, was decreased in the nodules; whereasthe activity of squalene synthase, the terminal regulating enzymeof cholesterol synthesis, remained unchanged. The dolichol speciesin nodular tissue were redistributed towards the longer chainlength species. One factor regulating the chain length of thepolyisoprene products formed in vitro was shown to be the ratioof the concentrations of isopentenyl pyrophosphate: farnesylpyrophosphate employed. Other regulatory factors in the terminalsteps of this biosynthetic pathway appear to determine the amountsand nature of the final isoprenoid compounds formed in vivo.In contrast to the microsomal trans-prenyltransferase activity,which was unchanged, the activity of nonaprenyl-4-hydroxybenzoatetransferase, an enzyme participating in ubiquinone synthesis,was greatly elevated. The alterations observed in the activitiesof enzymes in the mevalonate pathway can at least partiallyexplain the increased levels of dolichol and ubiquinone andthe unchanged level of cholesterol found in liver nodules. Itis reasonable to propose that this modified mevalonate metabolismwill render nodular cells resistant to certain toxic factorsand prone to cell proliferation.