Cytoplasmic accumulation of ditercalinium in rat hepatocytes and induction of mitochondrial damage.
Ditercalinium (NSC 335153), a 7H-pyridocarbazole dimer, is a bis-intercalating agent whose mechanism of action differs from that of other mono-intercalating compounds, such as ellipticine derivatives. After a Phase I clinical trial, where irreversible hepatotoxicity was the dose-limiting side-effect, we have reinvestigated the disposition of ditercalinium in rats after i.v. administration. Tissue distribution of the tritiumlabeled drug was studied during 5 weeks. The drug distributed very quickly into tissues, and accumulated mostly in liver and kidneys. A much slower clearance followed, with a half-life greater than 7 days. The present study raises the question of whether ditercalinium, a biscationic lipophilic agent, exerts a direct mitochondria interaction both in vitro and in vivo. Fluorescence microscopy on rat tissue cryosections, after drug administration, showed that the major cellular site of drug accumulation corresponds to mitochondria. The mitochondrial probe 3,3'-diethyloxadicarbocyanine confirmed the mitochondrial localization of ditercalinium. An identical fluorescent pattern was found in cultured rat hepatocytes. These fluorescent granulation patterns suggest mitochondrial damage. To further study cell alterations, ultrastructural changes in rat liver and kidneys were observed with selective mitochondrial damage while nuclei remained apparently normal. The same observations were made in rat hepatocyte cultures. Therefore, the accumulation of ditercalinium in tissues and, more particularly, in mitochondrial probably plays an important role in ditercalinium-induced toxicity.
Fellous
R
R
Unités de Biochimie-Enzymologie et de Physicochimie Macromoléculaire, (URA 158 CNRS, U140 INSERM) Institut Gustave-Roussy Villejuif, France.
Coulaud
D
D
el Abed
I
I
Roques
B P
BP
Le Pecq
J B
JB
Delain
E
E
Gouyette
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002227:Carbazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D005453:Fluorescence; D007364:Intercalating Agents / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; C042804:ditercalinium