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Combined toxic effects of irinotecan and delta-9-tetrahydrocannabinol in rat liver: an introductory study using DNA integrity and oxidative stress markers

The use of cannabinoid-based preparations by cancer patients raises concern whether delta-9-tetrahydrocannabinol (THC) can modulate or even compromise the effectiveness of concurrently administered anticancer drugs. Irinotecan (IRI) is a type of drug that causes various severe adverse effects such as diarrhoea, gastrointestinal toxicity and myelosuppression. Newer reports point to hepatotoxicity being an underestimated but important IRI side effect as well. This study focused on the evaluation of potentially detrimental interactions of IRI and THC in the liver of Wistar rats. Male rats were concomitantly exposed to IRI (at 100 mg/kg b.w., administered once i.p.) and THC (administered repeatedly for 1, 3 and 7 days per os at 7 mg/kg b.w.). Single IRI, THC and control groups were studied in parallel. We estimated changes in body and liver weight caused by the treatments, evaluated the level of primary DNA damage in hepatocytes using the alkaline comet assay, and evaluated the level of lipid peroxidation and catalase (CAT) activity. Changes in body weights and liver weights observed after the treatments suggest that all of the compounds at the tested doses and the applied experimental schedule produced acute toxicity and diminished the overall fitness of the exposed compared to control rats. It was most pronounced in rats administered a combined treatment. DNA damage was the most pronounced after 3-day treatment, and its highest level was observed in hepatocytes of single IRI-treated rats, followed by those given combined treatment. In contrast to 3-day, 7-day treatment with single THC slightly impaired hepatocyte DNA integrity. Rats given combined treatment demonstrated increased lipid peroxidation and higher CAT levels than those administered single IRI, at both time points, which may indicate that combined treatment induced more intense oxidative stress. Our findings provide evidence regarding a significant synergic enhancement of IRI toxicity caused by THC intake, which was confirmed using all of the applied biomarkers. Nevertheless, since we tested only one IRI and THC dose, further studies are required to further clarify their mutual interactions.

Acute toxicity ; Lipid peroxidation ; Oxidative stress ; Synergic enhancement ; Hepatotoxicity

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