Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro.
It has been shown previously that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) such as compactin and lovastatin suppress human lymphocyte functions in vitro (Cuthbert and Lipsky, 1981; Cutts and Bankhurst, 1989). Although it is not fully understood what inhibitory role the HMG-CoA RIs perform in causing this suppression, we show in this study that a certain inhibition threshold (inhibition level > 90%) of lymphocytic HMG-CoA reductase is required for the HMG-CoA RIs to attain effective inhibitory action in human lymphocyte lymphocyte functions in vitro. Thus the inhibitory activity of simvastatin, a lipophilic inhibitor, on sterol synthesis (HMG-CoA reductase activity) in lymphocytes was as much as 430 times more potent than that of pravastatin sodium, a hydrophilic inhibitor (IC50; 0.013 microM and 5.6 microM, respectively), and although pravastatin sodium and simvastatin at concentration levels of 10 and 0.016 microM respectively, inhibited the sterol synthesis in just over 50%, they failed to inhibit the lymphocyte functions. Significant inhibition (P < 0.01) of lymphocyte functions, including lymphocyte proliferative response to a variety of stimuli and activated natural killer-cell cytotoxicity, was demonstrated only when greater than 90% of the sterol synthesis in lymphocytes was inhibited by either simvastatin or simvastatin sodium salt at concentrations above 2 microM. This simvastatin-induced inhibition of lymphocyte functions was almost completely reversed by the addition of a 1 mM solution of mevalonate. Although simvastatin at a lower clinical blood concentration of 0.016 microM failed to inhibit either lymphocyte functions or HMG-CoA reductase activity sufficiently, at this level it caused a significant increase in cyclosporin A-induced suppression of T-cell response. These results infer that insufficient inhibition (in the 50% region) of HMG-CoA reductase activity by a low clinical blood concentration of HMG-CoA RIs, could still render the lymphocytes susceptible to immunosuppressive treatments. Pravastatin sodium on the other hand, is inactive in inhibiting lymphocyte functions in vitro, and such inactivity can be explained solely of the basis of its failure to inhibit HMG-CoA reductase activity in lymphocytes sufficiently.
Kurakata
S
S
Biological Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
Kada
M
M
Shimada
Y
Y
Komai
T
T
Nomoto
K
K
D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D008798:Mevalonic Acid / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology*; D019821:Simvastatin; D013261:Sterols / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D013261:Sterols; D016572:Cyclosporine; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid