HMG CoA reductase inhibitors affect Na(+)-H+ antiport activity in human lymphoblasts.
The Na(+)-H+ antiport is a membrane-bound glycoprotein that extrudes intracellular acid loads and regulates cellular volume. Cellular synthesis of the oligosaccharide side chains of glycoproteins is dependent on a supply of mevalonate, itself a product of the rate-limiting enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. The effect of two HMG CoA reductase inhibitors (simvastatin and 25-hydroxycholesterol) on intracellular pH and Na(+)-H+ exchange was therefore studied. Inhibition of the Na(+)-H+ antiport by these agents led to a fall in intracellular pH but did not impair the regulatory volume increase response to a hypertonic stimulus. The inhibitory effect of simvastatin was prevented by mevalonate but not dolichol or squalene. The effect of 25-hydroxycholesterol was more complex and not easily reversed. Thus HMG CoA reductase inhibitors reduced the ability of human lymphoblasts to expel an intracellular acid load via the Na(+)-H+ antiport, although the response of the antiport to an osmotic stimulus was preserved.
Ng
L L
LL
Department of Pharmacology, Leicester Royal Infirmary, University of Leicester, United Kingdom.
Davies
J E
JE
D001757:Blastomeres / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006888:Hydroxycholesterols / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007425:Intracellular Membranes / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D019821:Simvastatin; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017923:Sodium-Hydrogen Exchangers; C007997:25-hydroxycholesterol; D008148:Lovastatin; D019821:Simvastatin; D008798:Mevalonic Acid