Acetaminophen cytotoxicity in mouse eye: mitochondria in anterior tissues are the primary target

Acetaminophen (APAP) injected into C57BL/6 mice (cytochrome P450 inducer-responsive strain) that had been pretreated with b-naphthoflavone (BNF) produced ocular tissue damage, including cataract. Our previous histocytochemical studies showed that tissue damage spread in association with the flow of the aqueous humor and appeared first in the ciliary epithelium, followed by the iris and corneal endothelium and, finally, the lens. The neural retina, retinal pigmented epithelium and choroid remained unaffected. A close examination of the affected tissues indicated that mitochondria are the primary target of APAP cytotoxicity. In order to investigate whether the respiratory capacity of mitochondria is more sensitive to APAP cytotoxicity than mitochondrial morphology, we determined in this work the oxygen uptake by eye tissues dissected from BNF-pretreated and APAP-injected C57BL/6 mice. Oxygen uptake by the ciliary body/iris decreased about 60% at 90 min and 85% at 120 min after APAP administration. The oxygen uptake was inhibited about 50% by 10 microM rotenone. Since the earliest sign of mitochondrial damage was noted at 120 min, the result indicates that mitochondrial energy dysfunction precedes morphological alterations. It was also observed that oxygen uptake by the retina remained unaffected at least for 120 min after APAP administration; therefore, it is evident that the retina and, possibly, other posterior tissues as well are resistant to APAP cytotoxicity, not only in their morphology but, also, in their capacity of mitochondrial energy metabolism.