Protection of mitochondrial genetic system against aflatoxin B1 binding in animals resistant to aflatoxicosis.
Administration of a single dose of aflatoxin B1 (AFB1) (6 mg/kg) to Sprague-Dawley rats results in a high level of modification of hepatic mitochondrial DNA (2.1 nmol of AFB1 adducts per mumol DNA-phosphate) and long-term inhibition of mitochondrial transcription and translation activities (N. Bhat et al., Cancer Res., 42: 1876-1880, 1982). Similar doses of AFB1 given to ICR mice and Syrian golden hamsters result in negligible to very low levels (0-06 nmol) of adducts in hepatic mitochondrial DNA. Intact mitochondria from rat liver can metabolize significant amounts of AFB1 (0.29 nmol/mg of protein) without externally added reduced nicotinamide adenine dinucleotide phosphate, and the metabolic activity is stimulated nearly 3-fold by Kreb's cycle intermediates (glutamate and malate), which support intramitochondrial reduced nicotinamide adenine dinucleotide phosphate production. Intact mitochondria from mice and hamsters, on the other hand, metabolize negligible or very low levels of AFB1 (0-0.1 nmol of AFB1 per mg of protein) even when intramitochondrial reduced nicotinamide adenine dinucleotide phosphate production is stimulated by the addition of Kreb's acids. Detergent-solubilized mitoplasts containing less than 1% microsome contamination from all three sources can catalyze the metabolic activation of AFB1 to electrophilic reactive forms as determined in an in vitro DNA binding assay at comparable levels (1.2-2.2 nmol of AFB1 bound per mumol of cytochrome P-450), suggesting that the low levels of AFB1 metabolism by intact mouse and hamster mitochondria and the relative resistance of macromolecular synthesis in these particles to added AFB1 may be due to mitochondrial membrane impermeability. In support of this possibility, AFB1 transported into mouse liver mitochondria through a liposome delivery system causes about 80% inhibition of protein synthesis.
D016604:Aflatoxin B1; D000348:Aflatoxins; D000818:Animals; D001692:Biological Transport; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004351:Drug Resistance; D008081:Liposomes; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
D000348:Aflatoxins; D008081:Liposomes; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1