Sterol synthesis in variant Chinese hamster lung cells selected for resistance to 25-hydroxycholesterol. Cross-resistance to 7-ketocholesterol, 20alpha-hydroxycholesterol, and serum.
Two lines of Chinese hamster lung (Dede) cells which are resistant to the killing effect of 25-hydroxycholesterol, and which grow to confluence in its presence, have been isolated. One of the resistant lines exhibited a high to normal growth rate and normal levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34) activity and sterol synthesis in the presence of concentrations of 25-hydroxycholesterol that caused nearly complete suppression of these functions in wild type cells. The other variant line showed partial resistance to the inhibitory effects of the diol upon cell growth, sterol synthesis, and HMG-CoA reductase activity. The resistant phenotypes remained stable when the cells were maintained in the absence of the selecting agent. The Km (HMG-CoA), thermal stability, and susceptibility to inhibition by Mg2+ and ATP of HMG-CoA reductase were unaltered in both of the resistant lines. The two lines selected for growth in the presence of 25-hydroxycholesterol were also resistant to the inhibitory effects of 7-ketocholesterol, 20alpha-hydroxycholesterol, and serum upon HMG-CoA reductase and sterol synthesis, suggesting that suppression of cholesterol synthesis by these inhibitors involves a common step.
D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D003470:Culture Media; D004351:Drug Resistance; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007653:Ketocholesterols; D007700:Kinetics; D010743:Phospholipids / Q000096:biosynthesis; D013261:Sterols / Q000096:biosynthesis*
D003470:Culture Media; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D010743:Phospholipids; D013261:Sterols; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C003001:7-ketocholesterol