| Hydroxylated Polychlorinated Biphenyls as Inhibitors of the Sulfation and Glucuronidation of 3-Hydroxy-Benzo[a]pyrene Peter van den Hurk,1* Gerhard A. Kubiczak,2 Hans-Joachim Lehmler,2 and Margaret O. James1 1Department of Medicinal Chemistry, University of Florida, Gainesville, Florida, USA; 2Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, Kentucky, USA Abstract
Polychlorinated biphenyls (PCBs) can be metabolized by cytochromes P450 to hydroxylated biotransformation products. In mammalian studies, some of the hydroxylated products have been shown to be strong inhibitors of steroid sulfotransferases. As a part of ongoing research into the bioavailability of environmental pollutants in catfish intestine, we investigated the effects of a series of hydroxylated PCBs (OH-PCBs) on two conjugating enzymes, phenol-type sulfotransferase and glucuronosyltransferase. We incubated cytosolic and microsomal samples prepared from intestinal mucosa with 3-hydroxy-benzo[a]pyrene and appropriate cosubstrates and measured the effect of OH-PCBs on the formation of BaP-3-glucuronide and BaP-3-sulfate. We used PCBs with 4, 5, and 6 chlorine substitutions and the phenolic group in the ortho, meta, and para positions. OH-PCBs with the phenolic group in the ortho position were weak inhibitors of sulfotransferase ; the median inhibitory concentration (IC50) ranged from 330 to 526 µM. When the phenol group was in the meta or para position, the IC50 was much lower (17.8-44.3 µM) . The OH-PCBs were more potent inhibitors of glucuronosyltransferase, with IC50s ranging from 1.2 to 36.4 µM. The position of the phenolic group was not related to the inhibitory potency: the two weakest inhibitors of sulfotransferase, with the phenolic group in the ortho position, were 100 times more potent as inhibitors of glucuronosyltransferase. Inhibition of glucuronosyltransferase by low concentrations of OH-PCBs has not been reported before and may have important consequences for the bioavailability, bioaccumulation, and toxicity of other phenolic environmental contaminants. Key words: biotransformation, enzyme inhibition, polychlorinated biphenyls, sulfotransferase, UDP-glucuronosyltransferase, xenobiotics. Environ Health Perspect 110:343-348 (2002) . [Online 1 March 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110p343-348vandenhurk/ abstract.html Address correspondence to P. van den Hurk, Department of Medicinal Chemistry, College of Pharmacy, University of Florida, PO Box 100485, 1600 SW Archer Road, Gainesville, FL 32610 USA. Telephone: (352) 856-1971. Fax: (352) 846-1972. *Current address: Department of Environmental Toxicology, Clemson University, PO Box 709, Pendleton, SC 29670 USA. Telephone: (864) 646-2186. Fax: (864) 646-2277. E-mail: pvdhurk@clemson.edu We thank L. Rowland-Faux for help with preparing cytosol and microsomes. This study was supported by grants ES 05781, ES 07375, and ES 07380 from the National Institute of Environmental Health Sciences. Received 20 June 2001 ; accepted 16 October 2001.
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