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Properties of Hypolipidemic Peroxisome Proliferators in the Lymphocyte [³H]Thymidine and Salmonella Mutagenesis Assays¹

Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611 and Department of Toxicology, SRI International, Menlo Park, California 94025

Several hypolipidemic peroxisome proliferators have demonstrated carcinogenic activity in rodent species. Six of these hypolipidemic drugs have now been examined for their ability to induce damage in cellular DNA. Damage to DNA was evaluated by alteration in rates of [³H]thymidine incorporation into replicating DNA of in vitro cultures of proliferating lymphocytes and by mutagenic activity in the Salmonella/microsome assay. Both in the absence and presence of liver S-9 microsomal preparation, the hypolipidemic drugs ethyl--p-chlorophenoxyisobutyrate (clofibrate), 2-methyl-2-[p-(1,2,3,4-tetrahydro-1-naphthyl)phenoxy]propionic acid (nafenopin), 1-methyl-4-piperidylbis(p-chlorophenoxy)acetate (SaH-42-348), 2-chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (tibric acid), [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643), and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-ß-hydroxyethyl)acetamide] (BR-931) suppressed the rate of [³H]thymidine incorporation into replicating DNA in primary cultures of concanavalin A-stimulated C57BL/6J splenic lymphocytes. However, inhibition by hypolipidemic drugs of [³H]-thymidine incorporation into replicating DNA was reversed by incubation of drug-treated lymphocytes for 3 hr in fresh culture medium without hypolipidemic drug. This was in contrast to lymphocytes treated with the known DNA-damaging carcinogens methylnitrosourea or benzo(a)pyrene, in which the rate of [³H]thymidine incorporation into replicating DNA was increasingly suppressed during 3-hr incubation of treated lymphocytes without carcinogen. Furthermore, no mutagenic activity was detected in the Salmonella/microsome assay using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 for the drugs clofibrate, nafenopin, SaH 42-348, Wy-14,643, or BR-931 either in the absence or presence of liver S-9 microsomal preparation. Results obtained with the lymphocyte [³H]thymidine and the Salmonella mutagenesis assays therefore suggest that the hypolipidemic drugs either in the absence or presence of liver microsomes do not interact with and damage cellular DNA. Whether mutagenic metabolites are generated by hypolipidemic drug-induced liver peroxisomes remains to be elucidated.

¹ This work was supported by Grant 78-71 from the American Cancer Society, Illinois Division, USPHS Research Grant GM-23750, and USPHS Contract N01-CP 33394 from the Division of Cancer Cause and Prevention, National Cancer Institute.

² To whom requests for reprints should be addressed, at the Department of Pathology, Northwestern University, 303 East Chicago Ave., Chicago, Ill. 60611.

³ Present address: Genetic Toxicology Division, Genex Corporation, 6110 Executive Blvd., Rockville, Md. 20852.

Received 7/ 2/79. Accepted 9/27/79.

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