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Michelle M. Tabb,¹ Vladyslav Kholodovych,² Felix Grün¹, Changcheng Zhou,¹ William J. Welsh,² and Bruce Blumberg¹

¹Department of Developmental and Cell Biology, University of California, Irvine, California, USA; ²University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School and The UMDNJ Informatics Institute, Piscataway, New Jersey USA

Abstract
Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR) , inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk. Key words: metabolism, polychlorinated biphenyls, PXR, SXR, xenobiotic. Environ Health Perspect 112:163-169 (2004) . doi:10.1289/ehp.6560 available via http://dx.doi.org/ [Online 24 October 2003]

Address correspondence to B. Blumberg, Department of Developmental and Cell Biology, University of California, 5205 McGaugh Hall, Irvine, CA 92697-2300 USA. Telephone: (949) 824-8573. Fax: (949) 824-4709. E-mail: Blumberg@uci.edu

We thank J. Kanno, T. Iguchi, L. Guillette, C. Zilinski, and members of the Blumberg laboratory for critically reading the manuscript, and B. Forman and I. Dussault for plasmids.

Normal human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System, (Pittsburgh, PA) funded by National Institutes of Health (NIH) Contract N01-DK-9-2310. This study was supported by grants from the U.S. Environmental Protection Agency (STAR G1T1 0704) and the National Cancer Institute (CA-87222) to B.B. M.M.T was supported by a training grant from the NIH (Ruth L. Kirschstein NRSA T32 HD-07029) .

The authors declare they have no competing financial interests.

Received 2 July 2003 ; accepted 23 October 2003.