Alterations of drug-induced toxicity in the mouse lymphoma assay by a rat hepatic microsomal metabolizing system (S-9).
Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver microsomal metabolizing system (S-9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S-9 reduced cellular toxicity. For N-(4-hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S-9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S-9. HPR was metabolized by the S-9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S-9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S-9 or lymphoma cells. The reduced toxicity of this drug in the presence of S-9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D004988:Ethers, Cyclic / Q000633:toxicity*; D017313:Fenretinide; D007940:Leukemia L5178; D007942:Leukemia, Experimental; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D010880:Piperidines / Q000378:metabolism / Q000633:toxicity*; D011422:Propionates / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D009153:Mutagens; D010880:Piperidines; D011422:Propionates; D017313:Fenretinide; D014212:Tretinoin; C037813:fenoctimine; C017522:methyl 2-tetradecylglycidate