Direct effect of Taxol on free radical formation and mitochondrial permeability transition.

To elucidate the potential role of mitochondria in Taxol-induced cytotoxicity, we studied its direct mitochondrial effects. In Percoll-gradient purified liver mitochondria, Taxol induced large amplitude swelling in a concentration-dependent manner in the microM range. Opening of the permeability pore was also confirmed by the access of mitochondrial matrix enzymes for membrane impermeable substrates in Taxol-treated mitochondria. Taxol induced the dissipation of mitochondrial membrane potential (DeltaPsi) determined by Rhodamine123 release and induced the release of cytochrome c from the intermembrane space. All these effects were inhibited by 2.5 microM cyclosporine A. Taxol significantly increased the formation of reactive oxygen species (ROS) in both the aqueous and the lipid phase as determined by dihydrorhodamine123 and resorufin derivative. Cytochrome oxidase inhibitor CN(-), azide, and NO abrogated the Taxol-induced mitochondrial ROS formation while inhibitors of the other respiratory complexes and cyclosporine A had no effect. We confirmed that the Taxol-induced collapse of DeltaPsi and the induction of ROS production occurs in BRL-3A cells. In conclusion, Taxol-induced adenine nucleotide translocase-cyclophilin complex mediated permeability transition, and cytochrome oxidase mediated ROS production. Because both cytochrome c release and mitochondrial ROS production can induce suicide pathways, the direct mitochondrial effects of Taxol may contribute to its cytotoxicity.

[Galactose loading test in infants and small children suffering in recurrent bronchitis and other chronic illness (author's transl)]. / Galaktose-Belastungsuntersuchungen bei rezidivierender Bronchitis und anderen chronischen erkrankungen im Säuglings- und Kleinkindesalter.

The authors performed galactose loading tests in children suffering from chronic diseases: recurrent bronchitis vomiting, diarrhoea, milk-intolerance, somatic and mental retardation, cramps. In 32 of the 92 examined cases galactose levels rose until pathological, pseudo- diabetic levels. Stillbirth, cataract, hyperbilirubinaemia, convulsions occurred among family members of 10 patients. Galactose-1-phosphat-uridyl-transferase levels were decreased only in 4 of the 17 patients examined. In the other cases some different pathway of galactose metabolism is suspected. Complete remission of symptoms was achieved with diet devoid of milk sugar (lactose) in 29 patients: one infant died and two others remained mentally retarded. According to the examinations presented minor deviations of galactose metabolism cause clinical symptoms more frequently in early life as it was supposed until now.