Role of Mitochondria in Zone-Specific Toxicity to the Liver Lobule
Recently developed non-invasive optical and polarographic techniques along with ultramicrobiochemical methods were used to study the actions of allyl alcohol, a classic periportal toxin, on biochemical events in sublobular zones of the isolated perfused liver. Anterograde infusion of allyl alcohol (350 μM) for 60 minutes selectively injured periportal hepatocytes as indexed by uptake of trypan blue and by decreases in ATP/ADP ratios. Zone-specific decreases in ATP/ADP ratios were accompanied by impaired rates of oxygen uptake. Potassium cyanide (2 mM), an inhibitor of cytochrome oxidase, decreased ATP/ADP ratios but did not increase trypan blue uptake. Thus, disruption of ATP generation is a consequence rather than a cause of cellular injury due to allyl alcohol. Rates of oxidation of allyl alcohol to acrolein via alcohol dehydrogenase and depletion of cellular glutathione occurred equally in both zones of livers exposed to allyl alcohol indicating that zonal toxicity due to allyl alcohol was not due to differences in rates of metabolism of this compound.
Reversal of the direction of perfusions with allyl alcohol from anterograde to retrograde selectively damaged pericentral hepatocytes. Marked decreases in toxicity occurred when oxygen tension was lowered by decreasing the flow rate or perfusing with air-saturated buffer. Lipid peroxidation, as indexed by release of malondialdehyde from the perfused liver, was increased in the presence of allyl alcohol. Desferoxamine (100 μM), an iron trapping agent, (+)-cyanidanol-3 (400 μM), a radical scavenger, and allopurinol (1 mM), an inhibitor of xanthine oxidase, all prevented allyl alcohol-induced injury. These results indicate that oxygen tension is a key determinant of zonal toxicity due to allyl alcohol. Thus, zone-specific toxicity to the liver lobule by toxic agents that generate reactive oxygen species involves mitochondria in at least two ways. First, mitochondrial oxidations are the primary determinant of the oxygen gradient across the liver lobule. Rates at which reactive oxygen species are generated in sublobular zones are affected by this oxygen gradient. Second, the early decreases in ATP/ADP ratios and inhibition of respiration caused by allyl alcohol suggest that mitochondria are primary targets of reactive oxygen species generated by toxic chemicals.
KeywordsToxicity Glutathione Respiration Adduct Cyanide
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