Differential effects of polychlorinated biphenyl (PCB) mixtures and congeners on the disposition of thyroxine (T(4)) in rats

PCBs dramatically reduce serum T₄ in rats. This is thought to occur by induction of UDP-glucuronosyl transferase (UGT) enzymes and by increased biliary excretion of T₄-glucuronide. The purpose of this dissertation was to determine whether the effects of PCB mixtures on serum T₄ could be attributed to a type of PCB congener, and if these effects could be correlated with induction of hepatic UGT activity towards T₄, or with induction of transport proteins that may increase tissue uptake of T₄. Two Aroclor mixtures (1254 and 1242), PCB 126, a “2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-type inducer”, PCBs 95 and 99, “phenobarbital (PB)-type inducers”, PCB 118 a “mixed-type inducer”, and TCDD were evaluated. T₄ was significantly reduced in response to each of the treatments, but the most marked reductions occurred in response to Aroclor 1254, PCB 99 and PCB 118. Compounds with TCDD-like activity (Aroclor 1254, PCB 118, TCDD and PCB 126) significantly increased the biliary excretion of T₄-glucuronide and produced marked induction of hepatic UGT activity towards T₄. In contrast, disappearance of T₄ from plasma was dramatically increased by compounds with PB-like activity (Aroclor 1254, PCB 99 and PCB 118).{09}Aroclor 1254 and Aroclor 1242 both significantly increased the uptake of (125I]-T ₄ into liver. Organic anion transporting polypeptide 2 (Oatp2) protein levels in liver were suppressed by Aroclor 1254 and were not altered by Aroclor 1242, and neither PCB mixture significantly altered Oatp3 protein levels in liver. In contrast, both Aroclor 1254 and Aroclor 1242 produced significant increases in multidrug resistance associated protein 2 (Mrp2) levels. These data suggest that the effects of PCB mixtures on T₄ are not attributable to one type of congener, and reductions in serum T₄ in response to PCB congeners do not correspond with UGT activity toward T₄ or with increased biliary excretion of T₄-glucuronide. Enhanced plasma disappearance of T₄ by PCBs is due to an enhanced uptake of T₄ into the liver, but this cannot be explained by upregulation of Oatp2 or Oatp3. Upregulation of another transporter is probably responsible. However, upregulation of Mrp2 may contribute to increased biliary excretion of T₄-glucuronide produced by PCBs.