Mevalonate reverses the developmental arrest of preimplantation mouse embryos by Compactin, an inhibitor of HMG Co A reductase.

Hydroxymethyl glutaryl Co A reductase (HMG Co A reductase) is the key regulatory enzyme in the conversion of acetate to mevalonate. Mevalonate is the precursor for sterol and non-sterol isoprenes involved in membrane biogenesis, DNA replication and protein glycosylation. The influence of two inhibitors of HMG Co A reductase, Compactin (or ML236B) and an oxygenated sterol, Diosgenin, were tested on preimplantation development of mouse embryos. Compactin arrested development at about the 32-cell stage, leaving the blastomeres decompacted. Ultrastructural examination of the embryos revealed reduced membrane apposition but no major effects on cell organelles. There was however a predominance of nuclei with highly condensed chromatin. Glycosylation of proteins also appeared to be inhibited as shown by reduced incorporation of sugar precursors but not that of amino acids. The influence of Compactin was judged to be highly specific since only 10 micrograms/ml (0.08 mM) mevalonic acid abolished the effects of Compactin. Mevalonate in embryos may not be primarily utilized in the synthesis of sterols since a specific inhibitor of cholesterol synthesis, DL-4,4,10-beta-trimethyl-trans-decal-3-beta-ol had no detectable effect on development. The non-sterol isoprenes of mevalonate such as dolichol and isopentenyl adenine may play a more significant role during early development since the influence of Compactin resembled that previously described using tunicamycin, a specific inhibitor of dolichol mediated synthesis of N-glycosidically linked glycoproteins. Hence, lack of dolichol may partly be the cause of arrest of embryonic development by Compactin. Diosgenin caused embryonic arrest at about the 16-cell stage and the influence was not reversible by mevalonic acid. Cholesterol was able to rescue 50% of the embryos but the effect of Diosgenin could be non-specific and probably caused by its entry into the plasma membrane.