Irinotecan and Δ⁸-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers.

Ana Lucić Vrdoljak,Suzana Žunec,Irena Brčić Karačonji,Nino Fuchs,Ljerka Prester,Anja Mikolić,Nevenka Kopjar,Vedran Micek,Marijana Neuberg,Gordan Mršić,Andreja Jurič,Samir Čanović

doi:10.3390/molecules23061332

Abstract

There is growing interest regarding the use of herbal preparations based on Cannabis sativa for medicinal purposes, despite the poorly understood interactions of their main constituent Δ9-tetrahydrocannabinol (THC) with conventional drugs, especially cytostatics. The objective of this pilot study was to prove whether the concomitant intake of THC impaired liver function in male Wistar rats treated with the anticancer drug irinotecan (IRI), and evaluate the toxic effects associated with this exposure. IRI was administered once intraperitoneally (at 100 mg/kg of the body weight (b.w.)), while THC was administered per os repeatedly for 1, 3, and 7 days (at 7 mg/kg b.w.). Functional liver impairments were studied using biochemical markers of liver function (aspartate aminotransferase—AST, alanine aminotransferase—ALP, alkaline phosphatase—AP, and bilirubin) in rats given a combined treatment, single IRI, single THC, and control groups. Using common oxidative stress biomarkers, along with measurement of primary DNA damage in hepatocytes, the degree of impairments caused at the cellular level was also evaluated. THC caused a time-dependent enhancement of acute toxicity in IRI-treated rats, which was confirmed by body and liver weight reduction. Although single THC affected ALP and AP levels more than single IRI, the levels of liver function markers measured after the administration of a combined treatment mostly did not significantly differ from control. Combined exposure led to increased oxidative stress responses in 3- and 7-day treatments, compared to single IRI. Single IRI caused the highest DNA damage at all timepoints. Continuous 7-day oral exposure to single THC caused an increased mean value of comet tail length compared to its shorter treatments. Concomitant intake of THC slightly affected the levels of IRI genotoxicity at all timepoints, but not in a consistent manner. Further studies are needed to prove our preliminary observations, clarify the underlying mechanisms behind IRI and THC interactions, and unambiguously confirm or reject the assumptions made herein.

Highlights

We are witnesses to increased controversies associated with the use of Cannabis sativa products, which have slowly integrated into modern medicine
The multitude of effects they produce in an organism make C. sativa products attractive self-medications, used to relieve symptoms such as diarrhoea, abdominal pain, reduced appetite, chemotherapy-induced nausea, vomiting, etc. [3]
In spite of the fact that the tested dose was higher than the doses used in humans, we believe that this study design was appropriate, since we focused only on a rat model, which enabled us to control for confounding factors

Summary

Introduction

We are witnesses to increased controversies associated with the use of Cannabis sativa products, which have slowly integrated into modern medicine. Cannabis sativa is characterized by a complex phytochemical profile, which comprises more than 400 chemicals [1]. The most active component is ∆9 -tetrahydrocannabinol (THC) [2]. As a psychoactive compound [2], THC has a high abuse potential, so in most countries, the use of. C. sativa products is still prohibited and illegal. The multitude of effects they produce in an organism make C. sativa products attractive self-medications, used to relieve symptoms such as diarrhoea, abdominal pain, reduced appetite, chemotherapy-induced nausea, vomiting, etc. The multitude of effects they produce in an organism make C. sativa products attractive self-medications, used to relieve symptoms such as diarrhoea, abdominal pain, reduced appetite, chemotherapy-induced nausea, vomiting, etc. [3]

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Results

Conclusion