title: Chinese hamster cell mutant resistant to ML236B (Compactin) is defective in endocytosis of low-density lipo-protein.
abstract: A fungal metabolite, ML236B (Compactin), isolated from Penicillium citrinum, is a specific inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (EC 1.1.1.34). Three ML236B-resistant (ML236Br) mutants, MF-1, MF-2, and MF-3, were isolated from V79 after N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis. The fluctuation test showed 2.2 X 10(-6) mutants per cell per generation of a spontaneous mutation frequency of ML236Br clones. These ML236Br clones showed a four- to fivefold-higher resistance to the drug than did their parental V79. Radioactive acetate, but not mevalonate, incorporation into the sterol fraction increased about 10-fold in ML236Br clones in comparison with that in V79. The cellular level of HMG-coenzyme A reductase in three ML236Br mutants was found to be a few-fold higher than that of V79 when cultured in the presence of lipoproteins. The 125I-labeled low-density lipoprotein-binding assay showed binding activity in three ML236Br clones comparable to that of the parental V79 cells. By contrast, an internalization assay of 125I-labeled low-density lipoprotein into the cells showed significantly reduced activity in three ML236Br clones in comparison with V79.
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D006224:Cricetinae; D004351:Drug Resistance; D004705:Endocytosis; D005809:Genes, Regulator; D006888:Hydroxycholesterols / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007653:Ketocholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives*; D008798:Mevalonic Acid / Q000378:metabolism; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology*; D013261:Sterols / Q000096:biosynthesis
chemical_list: D000085:Acetates; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D009281:Naphthalenes; D013261:Sterols; C012258:mevastatin; C007997:25-hydroxycholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C003001:7-ketocholesterol; D008798:Mevalonic Acid