Irinotecan and Δ9-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers

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.

Genomic Instability in Peripheral Blood and Buccal Mucosal Cells of Marijuana Smokers: The Impact of Tobacco Smoke

“…Marijuana smoke condensates were mutagenic in the Ames test as well (Maertens et al, 2009). Some components induced cytogenetic damage in mammalian cells in vivo and in vitro (Maertens et al, 2013;Lucić Vrdoljak et al, 2019;Russo et al, 2019). Moreover, non-mammalian species demonstrated positive genotoxicity induced by marijuana (Parolini et al, 2017).…”

DNA Damaging Effects, Oxidative Stress Responses and Cholinesterase Activity in Blood and Brain of Wistar Rats Exposed to Δ9-Tetrahydrocannabinol

“…Without doubt, the experimental approach applied in the present study is a novel one, as there is a general lack of accurate data in this regard. With a previous pilot study [20], our group was the first to apply the alkaline comet assay to evaluate THC genotoxicity on a rat model. In our previous paper, we showed that continuous 7-day oral THC exposure produced low-level DNA damage in hepatocytes.…”

“…Since the present study was a pioneer in the assessment of potential THC genotoxicity on rodent white blood and brain cells using the comet assay, it is not possible to draw a parallel between our findings and other literature sources. We can only mention the conclusions of our previous comet assay study where the same THC dose was used [20]. They suggest that continuous 7-day oral exposure of rats to THC caused low-level DNA damage in liver cells.…”

“…This study represents a continuation of our research that focused on the evaluation of toxic effects of THC in vivo. The findings reported in our previous paper [20] suggested that administration of THC resulted in DNA damage in hepatocytes and provoked changes in levels of some functional liver markers and oxidative stress markers in exposed male Wistar rats. To further characterise the toxicity profile of THC and clarify its DNA damaging potential, in this study we estimated genome sensitivity of two other cell types, functionally and metabolically different from liver cells, following acute and repeated THC exposure.…”

Optimisation of a gas chromatography-mass spectrometry method for the simultaneous determination of tetrahydrocannabinol and its metabolites in rat urine

“…(1). Most of the aforementioned symptoms appear during therapy with the antitumor drug irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin, IRI, CPT-11) whose primary purpose was chemotherapy in metastatic colorectal cancer, but was also proven to be effective in treating lung cancer, ovarian cancer, leukaemia, and malignant glioma (2).…”