title: Glucuronidation of hydroxylated polychlorinated biphenyls (PCBs).
abstract: Polychlorinated biphenyls (PCBs) may be metabolized to hydroxylated compounds. While many of these metabolites are further converted to either the glucuronic acid or the sulfate conjugates by phase II enzymes, which facilitates their excretion, some hydroxylated PCBs persist in the body. This may reflect their inability to be conjugated. A possible role of uridine diphosphate glucuronosyl transferase (UGT) in the elimination of hydroxylated metabolites of PCBs was therefore investigated. Glucuronidation studies of PCB metabolites included ones which are eliminated with relative ease and also ones which are reported to be retained in blood. Liver microsomes, prepared from male Wistar rats treated by intraperitoneal injections of phenobarbital for 3 days (400 micromol/kg/day), were used as the source of UGT. Enzyme kinetics (V(max) and K(m)) were determined for each of the metabolites. The efficiency of glucuronidation (V(max)/K(m)) was found to vary from <3 to 116 microL/min/mg and was dependent on the structure of the metabolites. Substitution of chlorine atoms on the nonhydroxylated ring greatly lowered the V(max) of the enzyme, with substitution in the meta and para positions being least favorable for enzyme activity. Steric hindrance around the hydroxyl group by chlorines on adjacent carbon atoms did not play a major role. A weak relationship between the calculated dihedral angle (planarity), pK(a), log D, and enzyme activity was determined (r(2) < 0.5). However, a stronger relationship for the surface area and surface volume of the molecule was observed (r(2) >or= 0.5). This study explains in part why some PCB metabolites persist in the body.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky Chandler Medical Center, 306 Health Sciences Research Building, Lexington, Kentucky 40536-0305, USA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Tampal
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Tina
authors.initials: T
authors.lastname: Malmberg
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000378:metabolism* / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014535:Uridine Diphosphate Glucuronic Acid / Q000737:chemistry
chemical_list: D004785:Environmental Pollutants; D014535:Uridine Diphosphate Glucuronic Acid; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase