In vivo studies on the target tissue metabolism, covalent binding, glutathione depletion, and toxicity of 4-ipomeanol in birds, species deficient in pulmonary enzymes for metabolic activation

Alan R Buckpitt, Charles N. Statham, Michael R. Boyd

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Comparative studies on the target organ for covalent binding and toxicity by 4-ipomeanol, a furan derivative metabolically activated by and toxic to the nonciliated bronchiolar epithelial (Clara) cells in mammalian lung, were performed in birds. In birds, whose lungs lack the typical pulmonary ciliated and nonciliated bronchiolar cells and are deficient in enzymes necessary for the metabolic activation of 4-ipomeanol, the target organ for toxicity and covalent binding by 4-ipomeanol was the liver. Tissue damage was not observed in lungs or kidneys of either Japanese quail or roosters at any dose of 4-ipomeanol tested. Likewise, the levels of irreversibly bound 4-ipomeanol metabolites were highest in liver, with much lower levels in lungs, kidneys, and all other organs studied. In addition, toxic doses of 4-ipomeanol markedly depleted hepatic, but not pulmonary or renal glutathione in Japanese quail. The covalent binding of 4-ipomeanol metabolites and concomitant depletion of tissue glutathione in the liver were both time and dose dependent. In quail, over a dose range of 5 to 75 mg/kg, no dose threshold for covalent binding or hepatic damage which depended upon substantial glutathione depletion was observed. Pretreatment of quail with phenobarbital had no effect on liver cytochrome P-450 levels, nor did it have any effect on tissue covalent binding or toxicity by 4-ipomeanol. Although 3-methylcholanthrene pretreatment nearly tripled the microsomal cytochrome P-450 levels in quail liver, it had relatively little or no effect on the hepatic covalent binding or toxicity by 4-ipomeanol. Prior treatment with the drug metabolism inhibitor, piperonyl butoxide, markedly decreased the covalent binding, glutathione depletion, and the toxicity of 4-ipomeanol. Treatment of quail with diethylmaleate produced a dose-dependent depletion of hepatic, renal, and pulmonary glutathione, and it markedly increased hepatic covalent binding by 4-ipomeanol, but had no effect on renal or pulmonary covalent binding. Diethyl maleate markedly enhanced the hepatic necrosis by 4-ipomeanol. The results are consistent with the view that 4-ipomeanol is metabolized preferentially in quail liver to highly reactive metabolites which can be detoxified by glutathione. It appears unlikely however, that differences in detoxification via glutathione are the primary determinants of the remarkable tissue selectivity for covalent binding and toxicity of 4-ipomeanol in different animal species in vivo. The present studies support the view that the tissue selectivity of 4-ipomeanol resides primarily in the ability of the target tissue to rapidly metabolize 4-ipomeanol to its ultimate toxic metabolite(s). These investigations also suggest that the bird may be a potentially useful animal model in studies on the relationship of target organ toxicity to the formation of reactive metabolites by other chemicals requiring metabolic activation.

Original languageEnglish (US)
Pages (from-to)38-52
Number of pages15
JournalToxicology and Applied Pharmacology
Volume65
Issue number1
DOIs
StatePublished - 1982
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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