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Detection of Peroxisome Proliferators Using a Reporter Construct Derived from the Rat Acyl-CoA Oxidase Promoter in the Rat Liver Cell Line H-4-II-E

Xenometrix, Inc., Boulder, Colorado 80301

Peroxisome proliferators are nongenotoxic carcinogens capable of causing rapid transcriptional activation of genes comprising the rodent ß-oxidation pathway. Numerous compounds, such as hypolipidemic drugs, herbicides, plasticizers, and analgesics have been identified as peroxisome proliferators in rodents. We have developed a whole-cell in vitro assay to detect peroxisome proliferators in approximately 48 h. A promoter::chloramphenicol acetyltransferase (CAT) fusion construct for rat acyl-CoA oxidase (ACOX), the rate-limiting enzyme in the peroxisomal ß-oxidation pathway, was stably transfected into the rat liver cell line H-4-II-E. Treatment of the recombinant cell line (ACOX::CAT) with peroxisome proliferators, WY 14,643, clofibrate, di(2-ethylhexyl) phtalhate, and acetylsalicylic acid resulted in differential increases of CAT protein 48 h after exposure. Nonsteroidal anti-inflammatory drugs including ibuprofen, fenbupen, naproxen, and acetaminophen also up-regulated ACOX::CAT. Phorbol 12-myristate 13-acetate, a nongenotoxic carcinogen that is not classified as a peroxisome proliferator, also resulted in a slight induction of ACOX::CAT, consistent with the role of cell proliferation in tumor progression. The carcinogenic compounds 4-nitroquinoline N-oxide, ethyl methanesulfonate, diethylstilbestrol, and 2-aminoanthracene did not induce ACOX::CAT. Although the significance of peroxisome proliferators and their impact on humans is still unknown, the ability to identify them is of interest to the pharmaceutical and chemical industries. This assay was able to detect known peroxisome proliferators tested in approximately 48 h of exposure and to distinguish them from genotoxic carcinogens.

¹ To whom requests for reprints should be addressed, at Xenometrix, Inc., 2425 North 55^th Street, Boulder, CO 80301. Phone: (303) 447-1773; Fax: (303) 447-1758; E-mail: sbeard@xeno.com.

Received 10/10/96. Accepted 2/17/97.

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