Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Co gnex(R)), a simple acridine, is a reversible inhibitor of cholinesterase ac tivity available for the symptomatic treatment of Alzheimer's disease. Tacr ine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term i ll vitro exposures in isolated hepatocytes from humans and other species. T here is no clear relationship between transaminase elevation and Liver dama ge in humans, and prolonged drug exposure to animals does not result in hep atic insult, Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the end oplasmic reticulum (ER), aggregation of electron-dense structures within th e ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology an d function are unique to tacrine or not is unknown, as human hepatocytes ex posed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orang e, 9-aminoacridine, quinacrine and proflavin, In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane poten tial with parallel ultrastructural changes, The I-hydroxy and 7-hydroxy tac rine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, an d the non-acridine cholinesterase inhibitor eserine, did not induce charact eristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic, These data indicate th at the tacrine-like subcellular changes in hepatocytes are reproducible wit h other acridines and cause mitochondrial dysfunction in human hepatocytes, (C) 1998 John Wiley & Sons, Ltd.