Distribution and disposition of polychlorinated biphenyls (PCBs)

PCBs are persistent pollutants detected worldwide in various matrices of the environment. Both the parent congeners and their metabolites exert toxicological effects. This study investigates some properties of PCBs and/or their metabolites to explain their persistence in biological systems and their distribution and accumulation in some organs, like the brain, for example. I hypothesize that some aspects of distribution and disposition of PCBs and their persistence may be influenced by their binding to proteins and also by virtue of their being substrates for certain proteins like the transport proteins on the blood brain barrier and the enzyme proteins in the endoplasmic reticulum. Following studies were carried out.; 1. The role of the MDR transporter in restricting the entry of PCBs into the brain was examined. Non-coplanar PCBs, coplanar PCBs, and metabolites of coplanar PCBs were tested. All test compounds showed the ability to significantly increase the ATPase activity above its basal activity, suggesting binding to this transporter. However, using the L-MDR1 and L-mdr1a cells, neither PCB153 nor PCB 77 were transported by this transporter. Distribution studies of 14C-PCB 77 in mdr1a knockout mice and genetically matched wild-type mice also suggested PCB 77 was not a substrate for this transporter in vivo.; 2. A possible role of UDPGT in the elimination of hydroxylated PCBs was investigated. Enzyme kinetics were determined in vitro using liver microsomes as the source of enzyme. Comparison of conjugating efficiency for 15 PCB metabolites showed that those PCBs which are eliminated with relative ease were the ones which had a higher efficiency compared to those PCBs reported to be retained in the blood. A structure-activity relationship was also established.; 3. Binding of PCB 3 and PCB 77 to blood protein hemoglobin was studied in vivo. After 24 hours of dosing, both congeners showed covalent binding to globin with PCB 3 showing a 10 fold greater binding than PCB 77. Preliminary studies using LC-MS (electrospray) showed that both arene-oxide and quinones could be involved in binding to hemoglobin.; These studies support the concept that interaction of PCBs with proteins could influence their distribution and disposition.