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.

Effects of food natural products on the biotransformation of PCBs

“…Influence of a second flanking chlorine atom on the maximal rates of glucuronidation of polychlorobiphenylols in rat liver microsomes. Values taken from (Tampal et al, 2002) and (Daidoji et al, 2005). Concentrations of UDP-glucuronic acid (UDPGA) in channel catfish liver, proximal intestine and distal intestine.…”

“…Glucuronidation of several OH-PCBs has been studied in rat liver microsomes, with expressed human UGTs and in catfish intestinal and hepatic microsomes (Tampal et al, 2002;Daidoji et al, 2005;Sacco, 2006).…”

“…One study (Tampal et al, 2002) found apparent K m values for OH-PCB between 0.1 and 0.27 mM and V max from 0.31 to 31.3 nmol/min/mg, while another (Daidoji et al, 2005) reported OH-PCB apparent K m values between 0.03 and 0.14 mM and V max from 3 to 11 nmol/min/mg. The rat studies showed a general trend towards lower V max values with higher numbers of Cl atoms in the OH-PCB.…”

“…It is noteworthy that UDPGA concentrations of >2mM were needed for maximal rates of glucuronidation in rat hepatic microsomes. The apparent K m and V max values reported in Table 2 were obtained with UDPGA concentrations of 3 mM (Daidoji et al, 2005) or 4 mM (Tampal et al, 2002). Hepatic concentrations of UDPGA in rats are 0.2-0.4 mM (Goon and Klaassen, 1992), thus, actual rates of glucuronidation of OH-PCBs in rat liver are likely to be lower than the V max values.…”

Hepatocellular carcinoma and the risk of occupational exposure

“…Other studies in workers exposed to the PCB have reported an increased incidence of liver tumors [185][186][187][188] . Some possible mechanisms by which PCB can cause cancer have been assumed: Reactive oxygen species (ROS) is produced through the enzymatic oxidation or autoxidation of PCB; PCB determines the increased expression of genes responsible for inflammation and apoptosis in the liver; and PCB has "toxic" effects on certain genes, such as the loss of part of a chromosome and chromosome breakage [189][190][191][192][193][194][195][196][197][198][199] . ROS are also able to reduce telomerase activity which can determine telomere shortening.…”