Molecular Pharmacology, Vol 13, 719-725, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Repair in Vivo of Liver Deoxyribonucleic Acid Damaged by Hycanthone and Related Compounds

¹ Departments of Pathology and Biochemistry, Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Liver DNA damage and its subsequent repair in vivo, induced by the antischistosomal drug hycanthone methanesulfonate and its analogues, was studied by sedimenting DNA in alkaline and neutral sucrose gradients. Within 1 hr after administration to rats, hycanthone methanesulfonate (25 µg/g of body weight) caused liver DNA damage which could be monitored as slowly sedimenting DNA (compared with control) in alkaline as well as neutral sucrose gradients. By 24 hr the hepatic DNA of rats given hycanthone (100 µg/g of body weight) sedimented into the 2.3 M sucrose layer of the neutral sucrose gradients, suggesting repair of the DNA lesions. However, when the same DNA was sedimented in alkaline sucrose gradients, anomalies were observed even 48 hr after administration of the drug. At the same dosage, two analogues of hycanthone, the chloroindazole derivative and its N-oxide, which are less hepatotoxic, teratogenic, and mutagenic than hycanthone, failed to induce the DNA damage measurable as slowly sedimenting DNA in neutral sucrose gradients. Nonetheless, these two analogues, like hycanthone, intercalated into DNA. Niridazole (200 µg/g of body weight), another antischistosomal drug, neither intercalated into DNA non induced hepatic DNA damage measurable as slowly sedimenting DNA in either neutral or alkaline sucrose gradients.

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ACKNOWLEDGMENTS We thank Drs. E. Farber, E. Bueding, and Prema M. Rao for valuable discussions, and Margie Tartaglione and Barbara A. Briesmiester for their excellent technical assistance.