Development of Arsenic trioxide-induced hepatotoxicity model in mice according to the treatment protocol of acute promyelocytic leukemia

Arsenic trioxide (ATO) is used in treatment of APL. One of the major side effects of this drug is liver toxicity. So, introduction of an animal model for this toxic effect could be useful to evaluate hepato-protective compounds. As different hepatotoxic doses of arsenic have been reported in the literature, in this study we decided to develop a model of liver toxicity based on the protocol of ATO therapy in APL patients.

Considering the protocol of ATO therapy in APL patients (0.14 mg/day for 21 days) and FDA-suggested formula for dose translation between humans and animals, dose 1.7 mg/kg/day was used. To achieve the best time to take ATO administered without causing mortality, ATO was administered for 10 and 21 days to the male mice. At the end of the treatment period, liver tissue samples were dissected and then homogenized in physiologic buffer. The oxidative stress parameters including catalase and superoxide dismutase activity, lipid peroxidation and antioxidant capacity of the samples were determined using standard protocols. Damage to the liver tissue was determined by histopathological studies.

Histopathological examinations indicated severe damage to the liver in the 21-day treated period. The damage was accompanied with significant increase in the lipid peroxidation (p < 0.05), catalase activity (p < 0.05), and superoxide dismutase activity (p < 0.01) in the ATO treated mice for 21days.

Treatment of mice with ATO 1.7 mg/kg for 21 days could resemble ATO-induced hepatotoxicty in human.