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Alterations of drug‐induced toxicity in the mouse lymphoma assay by a rat hepatic microsomal metabolizing system (S‐9)
Author(s) -
Oldham James W.,
Preston Robert F.,
Paulson John D.,
Pritchard J. Frederick
Publication year - 1984
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2550040303
Subject(s) - toxicity , microsome , drug metabolism , pharmacology , chemistry , drug , metabolism , biotransformation , biochemistry , enzyme , biology , organic chemistry
Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver micro‐somal 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 (EC 50 ) 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. Moreover, the results illustrate that drug disposition studies may provide explanations for observed changes in drug‐induced toxicity.