Hepatic and extrahepatic bioactivation and GSH conjugation of aflatoxin B1 in sheep.
Whole-body autoradiography of [3H]aflatoxin B1 ([3H]AFB1) in lamb showed a localization of bound labelling, in addition to the liver, in the nasal olfactory and respiratory mucosa, in the mucosa of the nasopharynx, pharynx, oesophagus, larynx, trachea, bronchi and bronchioles and in the palpebral and bulbar conjunctiva. Microautoradiography revealed that the bound material was confined to specific cell types in extrahepatic tissues. Whole-body autoradiography also showed a labelling of pigmented tissues (such as the eye melanin), which can be ascribed to a melanin affinity of AFB1. In vivo experiments, performed with microsomal preparations of tissues from ewe and lamb showed that several of the extrahepatic tissues were more efficient than the liver in forming DNA-bound AFB1 metabolites. The nasal olfactory mucosa was by far the most effective tissue in this respect. AFB1 induced a high number of gene mutations in Salmonella typhimurium TA100 when incubated with supernatant preparations (9000 g) of the nasal olfactory mucosa, whereas incubations with preparations of the liver resulted in a lower effect. It has been reported that AFB1 can induce nasal tumours in sheep. When microsomal preparations of various tissues were incubated in the presence of reduced glutathione (GSH), but without any addition of cytosolic glutathione-S-transferase (GST), a drastic decrease in the AFB1-DNA binding was seen. Analyses of the water-soluble metabolites formed in the microsomal incubations supplemented with GSH showed fluorescent and ninhydrin-positive metabolites that were not present in the absence of GSH. These results indicate that sheep tissues have intrinsic microsomal GST or cytosolic GSTs associated with the microsomal fraction with a high capacity to catalyse the conjugation of bioactivated AFB1 to GSH. The results of the present study show that several extrahepatic tissues of sheep have a potent capacity to bioactivate AFB1 and also a high capacity to GSH conjugate the bioactivated AFB1.
Larsson
P
P
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
Busk
L
L
Tjälve
H
H
D016604:Aflatoxin B1 / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005069:Evaluation Studies as Topic; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D009152:Mutagenicity Tests; D012756:Sheep; D014316:Tritium
D014316:Tritium; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D005978:Glutathione