ENHANCED BILIARY EXCRETION OF THYROXINE GLUCURONIDE IN RATS PRETREATED WITH BENZPYRENE

Pretreatment of male or female rats with a single injection of benzpyrene 48 hr before cannulation of the bile duct produced a 3- and 4-fold increase in billary excretion of exogenously administered or endogenously produced labeled thyroxine. Almost all of the increase could be accounted for by enhanced excretion of thyroxine glucoronide. The effect of benzpyrene on thyroxine glucuronide excretion could not be demonstrated 4·5-9·5 hr after administration of the drug. This is in contrast to results obtained with compounds such as sodium salicylate and butyl-4-hydroxy-3,5-diiodobenzoate, which acutely promote increased biliary excretion of thyroxine by displacing it from its binding sites on plasma proteins. It also contrasts with the effect of drugs such as propylthiouracil, which increase thyroxine excretion in bile by blocking the major alternate pathway of metabolism, deiodination. Liver slices and homogenates from benzpyrene-treated rats displayed a several-fold increase in capacity to form thyroxine or o-aminopherol glucuronides. Although optimal conditions for assaying thyroxine glucuronyl transferase in liver homogenates were not achieved, the several-fold increase in glucuronyl transferase activity observed in liver homogenates from benzpyrene-treated rats seems best explained by assuming a corresponding increase in the level of the enzyme. The augmented biliary excretion of thyroxine in benzpyrene-treated rats is also best explained on the basis of an increase in liver glucuronyl transferase. Phenobarbital pretreatment produced a small increase in labeled thyroxine excretion in bile, which was not limited to the glucuronide alone. There was no effect on thyroxine conjugation in vitro, although a slight increase in o-aminophenol conjugation could be demonstrated. The slight effect which occurred in vivo with thyroxine appeared to be correlated with an increase in bile flow rather than with an increase in glucuronyl transferase. © 1968.