Effects of phenobarbital and 3-methylcholanthrene on the in vivo distribution, metabolism and covalent binding of 4-ipomeanol in the rat; implications for target organ toxicity

Abstract

The effects of phenobarbital (PB) and 3-methylcholanthrene (MC) on the distribution, metabolism and covalent binding of 4-ipomeanol were examined in the rat. An analysis of tissue extracts by high-pressure liquid chromatography (HPLC) showed that both treatments markedly decreased the concentrations of unmetabolized 4-ipomeanol at all times examined. PB treatment increased the urinary excretion of nonbound 4-ipomeanol metabolites, while MC treatment did not alter their excretion. Analysis of urine by HPLC indicated that the increased concentration of urinary metabolites found in the phenobarbital-treated rats was attributable primarily to an increased excretion of ipomeanol-4-glucuronide. These data indicate that the decreased pulmonary covalent binding and lethality of 4-ipomeanol in the rat after MC and PB were caused by alterations in the tissue distribution of the parent compound. Pulmonary concentrations of unmetabolized 4-ipomeanol were decreased by MC through an increased metabolism of 4-ipomeanol in the liver, primarily to toxic products that bind covalently in that tissue and lead to hepatoxicity. PB produced a similar decrease in unmetabolized 4-ipomeanol concentrations in lung but by an enhanced in vivo metabolism and clearance of 4-ipomeanol, primarily through a "nontoxic" pathway, glucuronidation, and did not lead to hepatotoxicity.