Tracing tissues with 4-ipomeanol-metabolizing capacity in rats.
Rats were given 3H-labelled 4-ipomeanol intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted with trichloroacetic acid, water and organic solvents, was performed to examine the disposition of unbound and bound radioactivity in various tissues. Microautoradiography with glutaraldehyde-fixed, resin-embedded material was used to investigate the cellular distribution of bound metabolites. Based on the data obtained from these experiments in vitro incubations with tissue-slices were carried out to examine the capacity by various tissues to form tissue-bound 3H from the 3H-labelled 4-ipomeanol and autoradiography of isolated organs after incubation with 3H-labelled 4-ipomeanol was performed to study the localization of radioactivity under in vitro conditions. The results showed a high formation of tissue-bound 3H in the lung in vitro and a localization of bound metabolites in several structures of the lung in vivo. In vitro formation of tissue-bound 3H was also found in the nasal olfactory and respiratory mucosa, the hard palate, the trachea, the liver and the kidney and this was also correlated with a localization of bound 3H in these tissues in vivo. Incubations of the lung, the nasal olfactory mucosa, the hard palate and the liver in CO- or N2-atmospheres or in the presence of the cytochrome P-450-inhibitor metyrapone showed decreased formation of tissue-bound 3H from the 3H-labelled 4-ipomeanol, indicating a role of cytochrome P-450 in the metabolism of 4-ipomeanol in the various tissues. The correlation between the in vitro capacity of various tissues to metabolize the 4-ipomeanol and the in vivo accumulation of tissue-bound metabolites in the same tissues indicate that a local bioactivation of the 4-ipomeanol takes place in these tissues in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
Larsson
P
P
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
Tjälve
H
H
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D005260:Female; D005612:Freeze Drying; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009092:Mucous Membrane / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism; D010159:Palate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012137:Respiratory System / Q000378:metabolism; D013729:Terpenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014316:Tritium
D013729:Terpenes; D014316:Tritium; C001470:4-ipomeanol