propylthiouracil and triiodothyronine-glucuronide

In normal rats, T3 glucuronide (T3G) is the major biliary T3 metabolite, but excretion of T3 sulfate (T3S) is greatly increased after inhibition of type I deiodinase, e.g. with 6-propyl-2-thiouracil (PTU). In this study, the fate of the T3 conjugates excreted with bile was studied to assess the significance of a putative enterohepatic circulation of T3 in rats. Conventional (CV) or intestine-decontaminated (ID) rats received iv [125I]T3G or [125I]T3S, the latter usually after pretreatment with PTU (1 mg/100 g BW). Radioactivity in plasma and bile or feces was analyzed by Sephadex LH-20 chromatography and HPLC. Within 1 h, 88% of injected T3G was excreted in bile of CV or ID rats, independent of PTU. About 75% of the injected T3S was excreted within 4 h in PTU-treated rats, in contrast to only 20% in controls. Up to 13 h after iv administration of T3G or T3S (+PTU) to intact ID and CV rats, fecal radioactivity consisted of more than 90% T3 in all CV rats, 95% of T3S in T3S-injected ID rats, and 30% T3 and 67% T3G in T3G-injected ID rats. In overnight-fasted CV rats injected with T3G, total plasma radioactivity rapidly declined until a nadir of 0.10% dose/ml at about 2.5 h, but radioactivity reappeared with a broad maximum of 0.12% dose/ml between 5.5-10 h. In the latter phase, plasma radioactivity consisted of predominantly I- and T3 in a ratio of 2:1. Reabsorption was diminished in fed CV rats and prevented in ID rats. Plasma T3 4-10 h after iv T3G injection to overnight-fasted CV rats was 12, 2, and 3 times higher than that in bile-diverted rats, fed CV rats, and ID rats, respectively, and similar to that 4 h after the injection of T3 itself. Total plasma radioactivity as well as plasma T3 6-13 h after iv administration T3S in PTU-treated rats were significantly increased in CV vs. ID rats, e.g. T3 0.016% vs. 0.005% dose/ml. These results demonstrate a significant enterohepatic circulation of T3 in rats in which bacterial hydrolysis of T3 conjugates excreted with bile plays an important role.

Topics: Animals; Bile; Blood Proteins; Decontamination; Enterobacteriaceae; Enterohepatic Circulation; Feces; Glucuronates; Intestines; Iodide Peroxidase; Iodine Radioisotopes; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

The liver metabolizes T4 by deiodination and conjugation to T4 glucuronide (T4G), but little information exists about the formation of T4 sulfate (T4S) in vivo. We have examined the excretion of T4G, T4S, T3 and rT3 glucuronide (T3G and rT3G) in bile, collected under pentobarbital anesthesia 0-8 h or 17-18 h after iv [125I]T4 injection to control and 6-propyl-2-thiouracil (PTU)-treated rats. Radioactivity in bile, plasma, feces, and urine was analyzed by Sephadex LH-20 chromatography and HPLC. PTU induced a 2-fold increase in the biliary excretion of total radioactivity (26.6% vs. 15.0% dose between 0-8 h; 2.0% vs. 1.0% dose between 17-18 h). Biliary metabolites, 17-18 h after T4 injection, in control vs. PTU rats amounted to (percent dose): T4G, 0.44 vs. 0.75; T3G, 0.19 vs. 0.07; rT3G, 0.02 vs. 0.15; and T4S, 0.06 vs. 0.32. Similar results were obtained for control rats when bile was collected between 7-8 h after iv T4. The excretion rate of T3G was lower and that of rT3G higher when bile was continuously collected for 8 h immediately after T4 administration, probably due to prolonged experimental stress. However, regardless of the period of bile collection, PTU induced a more than 24-fold decrease in the T3G/rT3G ratio and a 5-fold increase in T4S excretion. In the animals killed 18 h after T4 injection, PTU treatment increased plasma T4 retention by 50%, reduced urinary I- excretion by 74%, and increased fecal radioactivity by 47%. No conjugates were detected in feces, and the distribution of fecal T4:T3:rT3 was 70:18:2 in control and 68:7:6 in PTU-treated rats. The results indicate that 1) the glucuronidative clearance of T4 is not affected by PTU; 2) the T3G/rT3G ratio in bile is a sensitive indicator of type I deiodinase inhibition; 3) T4 undergoes significant sulfation in rats in vivo, and 4) biliary excretion of T4S is enhanced if its type I deiodination is inhibited.

Topics: Animals; Bile; Chromatography, High Pressure Liquid; Glucuronates; Propylthiouracil; Rats; Thyroxine; Triiodothyronine