Distribution and metabolism of the pulmonary alkylating agent and cytotoxin, 4-ipomeanol, in control and diethylmaleate-treated rats.
Diethylmaleate (DEM), an agent which depletes tissue glutathione (GSH), increased the covalent binding and toxicity of 4-ipomeanol [1-(3-furyl)-4-hydroxypentanone] in rats. The distribution of unmetabolized 4-ipomeanol-[5-14C] and its metabolites were studied in tissue extracts by high-pressure liquid chromatography (HPLC) in control and DEM-treated rats. At all time periods examined, DEM treatment produced no significant effect on the tissue distribution of unchanged 4-ipomeanol. In both groups, the relative tissue concentrations of unmetabolized 4-ipomeanol were in the order blood greater than lung greater than liver. In control rats, the relative tissue concentrations of nonbound, solvent-extractable 4-ipomeanol metabolites (hereafter referred to simply as "4-ipomeanol metabolites"), as well as the covalently bound 4-ipomeanol metabolites (hereafter referred to as "covalently bound 4-ipomeanol equivalents" to distinguish from all other metabolites) were in the order lung greater than liver greater than blood. The pulmonary levels of both the covalently bound 4-ipomeanol equivalents and the 4-ipomeanol metabolites were increased markedly by DEM treatment at all time periods examined. The total pool of urinary 4-ipomeanol metabolites was significantly decreased by DEM treatment, but the total amounts of excreted ipomeanol-4-glucuronide, the major metabolite of 4-ipomeanol in rats, were not significantly different in the control and DEM-treated rats. These data are consistent with the view that the increased pulmonary covalent binding and toxicity of 4-ipomeanol produced by diethylmaleate treatment in rats are due to the depletion of pulmonary GSH by the DEM and not a major DEM-induced alteration in the tissue distribution of the parent 4-ipomeanol.
D000818:Animals; D001665:Binding Sites; D005663:Furans / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013729:Terpenes / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*
D005663:Furans; D008298:Maleates; D013729:Terpenes; D014118:Toxins, Biological; C014476:diethyl maleate; D005978:Glutathione; C001470:4-ipomeanol