Multifunctional analysis of the interaction of anthralin and its metabolites anthraquinone and anthralin dimer with the inner mitochondrial membrane.

We studied the interaction of the antipsoriatic compound anthralin (1.8-dihydroxy-9-anthrone), and its metabolites anthraquinone (1.8-dihydroxy-9.10-anthraquinone) and anthralin dimer (1.8.1'.8'.-tetrahydroxy-10.10'-bis-9[10]-dianthrone) with the inner mitochondrial membrane. Mitochondrial membrane functions such as ubiquinone redox equilibria, redox status of iron sulfur clusters, cyanide-sensitive and cyanide-insensitive oxygen consumption, adenosine triphosphate (ATP) synthesis, ATP hydrolysis, and adenine nucleotide content of mitochondria were analyzed. Anthralin is an inhibitor of mitochondrial oxygen uptake in the presence of ADP and substrate (cyanide-sensitive respiration), inhibits ATP synthesis without affecting ATP hydrolysis, and depletes mitochondria of ATP. Anthralin dimer is a much weaker inhibitor of mitochondrial functions and anthraquinone is almost inactive. Anthralin, but not anthraquinone and anthralin dimer, reverses uncoupler stimulated oxygen consumption, stimulates cyanide-insensitive respiration, reduces mitochondrial ubiquinone-9 and -10 to the corresponding ubiquinols and reduces mitochondrial iron sulfur clusters. Anthralin may induce formation of reactive oxygen species by enhancing autoxidation of mitochondrial components and/or by catalyzed oxidation of anthralin. Taken together, anthralin acts as an electron donor to inner mitochondrial membrane associated redox components, inhibits the electron transport chain, and has an oligomycin-like effect. Anthralin dimer and anthraquinone do not function as electron donors and act by a different reaction mechanism. Respiratory measurements in human keratinocytes revealed similar results as obtained with isolated mitochondria. We suggest that modulation of membrane redox status may be a common concept of anthralin action in target cells such as keratinocytes and neutrophils.