RT Journal Article
SR Electronic
T1 Glucuronidation of Polychlorinated Biphenylols and UDP-Glucuronic Acid Concentrations in Channel Catfish Liver and Intestine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 623
OP 630
DO 10.1124/dmd.107.019596
VO 36
IS 4
A1 James C. Sacco
A1 Hans-Joachim Lehmler
A1 Larry W. Robertson
A1 Wenjun Li
A1 Margaret O. James
YR 2008
UL http://dmd.aspetjournals.org/content/36/4/623.abstract
AB Polychlorinated biphenylols (OH-PCBs) are potentially toxic polychlorinated biphenyl metabolites that can be eliminated by glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs). OH-PCBs with a 3,5-dichloro-4-hydroxy substitution pattern have been detected in blood from humans and wildlife, suggesting slow elimination. In this study we assessed the glucuronidation of 4-OH-PCBs with zero, one, or two chlorine atoms flanking the 4-hydroxyl group and zero to four chlorine atoms in the aphenolic ring in microsomes from channel catfish liver and proximal intestine. Product formation was quantitated with [14C]UDP-glucuronic acid (UDPGA). Physiological concentrations of UDPGA were measured in preparations of liver and intestine. When the OH-PCB concentrations were varied in the presence of saturating UDPGA concentrations, glucuronidation Vmax values were higher in hepatic than in intestinal microsomes (0.40–3.4 and 0.12–0.78 nmol/min/mg of protein, respectively), whereas the Km values were generally lower for intestine (0.042–0.47 mM) than for liver (0.11–1.64 mM). In both tissues Vmax values with 3,5-dichloro-4-OH-PCBs were lower than with the corresponding 3-chloro-4-OH-PCBs. Varying the UDPGA concentrations in the presence of saturating concentrations of OH-PCB showed that the Km for UDPGA was lower in intestine (27 μM) than in liver (690 μM). The measured concentration of UDPGA in catfish liver (246–377 nmol/g) was lower than the Km for UDPGA, suggesting that in vivo rates of glucuronidation may be suboptimal, whereas in intestine the measured UDPGA concentration (71–258 nmol/g) was higher than the Km for UDPGA. Although liver has a greater glucuronidation capacity than proximal intestine, the properties of intestinal UGTs in channel catfish enable them to efficiently glucuronidate low concentrations of OH-PCBs.