Revised Manuscript Received March 18, 1993 abstract: The human peroxisome proliferator activated receptor (hPPAR) was cloned from a human liver cDNA library. The cDNA exhibited 85% and 91% DNA and deduced amino acid sequence identity with mouse PPAR (mPPAR), respectively. The hPPAR gene was mapped on human chromosome 22 slightly telomeric to a linkage group of six genes andgenetic markers that are located in the general region 22ql2-ql3. 1. Cotransfection assays of mouse Hepa 1 cells were used to roughly compare the ability of hPPAR-and mPPAR-expressed cDNAs to frans-activate the acylCoA oxidase (ACO) PPAR response element located 5'upstream to the minimal thymidine kinase promoterdriving the expression of the chloramphenicol acetyl transferase (CAT) reporter gene. Both receptors elicited a response with the prototypical peroxisome proliferators nafenopin, clofibrate, and WY-14,643. Moreover, using cotransfection assays in which the CAT reporter plasmid contained the CYP4A6 gene response element rather than the ACO element, it was shown that hPPAR is capable of very efficently trans-activating a second PPAR response element. These results indicate that the PPAR is present in humans in a form that is functional and can trans-activate response elementsderived from two different genes, the rat ACO and the rabbit CYP4A6.

Peroxisome proliferators are a diverse group of chemicals which includes hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers (for a review, see Reddy and Lalwai (1983), Moody et al.(1991), and Green (1992)). Two major categories of peroxisome proliferator chemicals play a significant role in current society. The first, the fibrate class of hypolipidemic drugs, has been found to be effective at reducing thelevels of triglycerides and cholesterolin humans suffering from hyperlipidemia, a major risk factor for coronary heart disease (Thorp & Waring, 1962; Dujovne et al., 1970; Berioli et al., 1990). The second category relates to phthalate ester plasticizers used in the production of highly versatile flexible vinyl plastics (Reddy & Lalwai, 1983). Peroxisome proliferators seem to affect most mammalian species that have been tested. They induce hepatomegaly resulting from liver hyperplasia and an increase in the size and number of peroxisomes (Reddy & Lalwai, 1983). Nevertheless, on the basis of hypolipidemic drug dose required to produce recognizable peroxisome proliferation, mice and rats are considered to be highly responsive to these agents, developing hepatocellular carcinoma following long-term drug administration, hamstershave intermediate responses, and guinea pigs, marmosets and other nonhuman primates are weakly responsive (Eacho et al., 1986; Lake et al., 1989; Reddy et al., 1984).