Effect of Butylated Hydroxyanisole on Hepatic Glucuronidation and Biliary Excretion of Drugs in Mice

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Abstract
Inhibition of glucuronidation by depletion of UDP-glucuronic acid from liver impairs the hepatobiliary transport of glucuronidated xenobiotics. However, it is not known if enhancement of hepatic glucuronidation increases the biliary excretion of these compounds. Therefore, the effect of treatment with butylated hydroxyanisole (BHA), which increases hepatic glucuronidation capacity, on the biliary excretion of compounds undergoing glucuronidation was studied in mice. BHA-feeding (1% for 10 days) increased hepatic UDP-glucuronic acid content by 240% and enhanced hepatic UDP-glucuronosyltransferase activities (expressed per kg body weight) toward valproic acid, phenolphthalein, iopanoic acid and bilirubin 220, 180, 120 and 60%, respectively. BHA treatment did not influence the biliary excretion of unmetabolized cholephils, phenol-3,6-dibromphthalein disulphonate and phenolphthalein glucuronide, but enhanced that of phenolphthalein (+108%), iopanoic acid (+63%) and bilirubin (+33%) as glucuronides. However, these increases were apparent only in the initial phase of excretion. In contrast, BHA markedly decreased (−43%) the biliary excretion of valproic acid glucuronides. Simultaneously, BHA increased the urinary excretion of the glucuronides of phenolphthalein (+48%), iopanoic acid (+450%) and valproic acid (+150%). A shift in the distribution of iopanoic acid and valproic acid and metabolites from liver to kidney was also apparent in BHA-fed mice. Thus, enhanced glucuronidation does not facilitate the biliary excretion of all glucuronidated compounds and only transiently increases others. It is likely that this phenomenon is the result of the glucuronides readily entering the plasma and being excreted by the kidney.