Suppression of lymphoid cell function in vitro by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by lovastatin.
A 3-hydroxy-3-methylglutaryl Coenzyme A (HMG CoA) reductase inhibitor, lovastatin, has recently been approved for the treatment of hypercholesterolemia. However, the product of HMG CoA reductase, mevalonate (MVA), is an early precursor not only for cholesterol but also for several other essential molecules. Since HMG CoA reductase is found in lymphoid cells, the potential alteration of lymphoid cell function by lovastatin was examined. At doses equivalent to pharmacological concentrations, exposure to lovastatin for 7 days inhibited phytohemagglutinin-stimulated proliferation by 25-54% and natural killer cell cytotoxicity by 25-57%. At higher concentrations (10 microM) for shorter periods of time (48 h), lovastatin inhibited phytohemagglutin and Concanavalin A-stimulated proliferation by 83% and 38% respectively, natural killer cell cytotoxicity by 93%, and interferon gamma production by 98%. The inhibition of these parameters could be largely reversed by the addition of MVA; however, MVA itself was not a stimulant. Overall, the in vitro inhibitions seen with lovastatin raise a concern about potential in vivo alteration of lymphoid cell function seen with long term administration of HMG CoA reductase inhibitors.
Cutts
J L
JL
Department of Medicine, University of New Mexico School of Medicine, Albuquerque 87131.
Bankhurst
A D
AD
D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000188:drug therapy; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008148:Lovastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007376:Interleukin-2; D008934:Mitogens; D007371:Interferon-gamma; D008148:Lovastatin; D008798:Mevalonic Acid