Binding of 3H-metronidazole in olfactory, respiratory and alimentary epithelia in rats.
Whole-body autoradiography of 3H-metronidazole in rats showed retention of bound metabolites in the epithelia lining the olfactory part of the nose, the tongue, the gingiva, the palate, the pharynx, the oesophagus and the forestomach. In vitro microautoradiography in O2- and N2-atmosphere with some of these tissues indicated reductive formation of bound metabolites in specific cells of the epithelia. Studies with subcellular fractions of the nasal olfactory mucosa showed formation of DNA- and protein-bound metronidazole metabolites. A lower bioactivating capacity was found in experiments with the liver. The bioactivation was dependent on N2-atmosphere, and presence of the P450-inhibitor metyrapone or GSH in the incubation media depressed the protein-binding of metronidazole both in the nasal olfactory mucosa and the liver. These data indicate that the bioactivation is partly P450-dependent and GSH may play an important role in scavaging the bioactivated drug. The epithelial cells with a capacity to bioactivate metronidazole may be potential targets for negative effects of the drug. Whole-body autoradiography also showed a strong binding of radioactivity in the contents of caecum and colon. This can be considered to be due to reductive bioactivation of metronidazole by the intestinal microorganisms and reflects the principal site of action of the drug.
Larsson
P
P
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, SLU, Uppsala, Sweden.
Cybulski
W
W
Tjälve
H
H
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D008795:Metronidazole / Q000378:metabolism*; D008797:Metyrapone / Q000494:pharmacology; D009584:Nitrogen / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution; D014316:Tritium
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011506:Proteins; D014316:Tritium; D008795:Metronidazole; D005978:Glutathione; D009584:Nitrogen; D008797:Metyrapone