Hydroxylated polychlorinated biphenyls as inhibitors of the sulfation and glucuronidation of 3-hydroxy-benzo[a]pyrene.
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 microM. When the phenol group was in the meta or para position, the IC50 was much lower (17.8-44.3 microM). The OH-PCBs were more potent inhibitors of glucuronosyltransferase, with IC50s ranging from 1.2 to 36.4 microM. 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.
van den Hurk
Peter
P
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA. pvdhurk@clemson.edu
Kubiczak
Gerhard A
GA
Lehmler
Hans-Joachim
HJ
James
Margaret O
MO
D000818:Animals; D015239:Arylsulfotransferase / Q000187:drug effects / Q000378:metabolism*; D001580:Benzopyrenes / Q000378:metabolism*; D001682:Biological Availability; D001711:Biotransformation; D002397:Catfishes / Q000502:physiology; D004064:Digestive System / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D011078:Polychlorinated Biphenyls / Q000009:adverse effects* / Q000493:pharmacokinetics
D001580:Benzopyrenes; D004785:Environmental Pollutants; C021338:3-hydroxybenzo(a)pyrene; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D015239:Arylsulfotransferase