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Diaziquone-induced Cytotoxicity in Isolated Rat Hepatocytes¹

Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 1A1, Canada

2,5-Diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone (AZQ) is a lipid-soluble antitumor agent. The following evidence using isolated rat hepatocytes as a model for cytotoxicity studies suggests that, under aerobic conditions, AZQ participates in futile oxidation-reduction cycling and oxygen activation. The H₂O₂ formed can mediate oxidative stress cytotoxicity in compromised cells. (a) Addition of AZQ to hepatocytes causes the stoichiometric oxidation of glutathione (GSH) to oxidized glutathione. No subsequent reduction back to GSH occurred. This was found to be the result of reversible inactivation of glutathione reductase by AZQ. The extent of GSH oxidation increased with AZQ concentration. (b) Cytotoxicity occurred when AZQ concentrations were sufficient to completely deplete GSH. (c) Addition of AZQ to hepatocytes enhanced cyanide-resistant respiration. (d) If the hepatocytes were compromised with azide or cyanamide to inhibit catalase, cytotoxicity was increased 10-fold or 100-fold if ascorbate was also present. (e) AZQ readily induced Ca²⁺ release by energized mitochondria. Ascorbate markedly enhanced the effectiveness of AZQ, and catalase delayed Ca²⁺ release. H₂O₂ formed by aerobic oxidation-reduction cycling of AZQ may therefore cause mitochondrial Ca²⁺ release.

¹ This research was supported by a grant from the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed.

Received 11/16/88. Revised 6/29/89. Accepted 7/21/89.

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