In vitro investigation of the possible toxicological mechanisms behind the adverse reactions of Garcinia cambogia (Gaertn.) Desr. extracts in human cholangiocytes

Background. Garcinia cambogia (Gaertn.) Desr. is a plant from the Clusiaceae family, traditionally used to treat gastrointestinal disorders [1]. It is currently used in dietary supplements for weight loss and weight maintenance due to the presence of (-)-hydroxycitric acid (HCA), which has been reported to affect food intake, stimulates fat oxidation and energy expenditure, reduce fatty acid synthesis and modulates serotonin levels [2-3]. Despite perceived safety, serious adverse effects, including hepatotoxicity and cases requiring liver transplantation, have been associated to the consumption of garcinia-based food supplements [4]. Given that the majority of individuals consuming weight loss supplements are affected by overweight or obesity, a condition associated with chronic low-grade systemic inflammation [5], this study investigated the possible toxicity of an aqueous extract from G. cambogia fruit, containing 60% w/w hydroxycitric acid, and the underlying molecular mechanisms in cell models of the gastro-intestinal tract under inflammatory conditions. Methodologies. To perform the study, H69 intrahepatic cholangiocytes were used. The cells were challenged with the pro-inflammatory cytokine IL-6, which is typically increased in experimental models of obesity [6], in order to mime inflammatory conditions. Then the cells were treated with progressive concentrations of the extract under different protocols of exposure. After treatment, cell viability and intracellular oxidative stress were determined [4]. Moreover, the LDH release, which is measure of the treatment impact on the membrane integrity, and the possible impairment of Nrf2 expression, a key factor involved in cell defence, were measured. Results. Under our experimental conditions, the 6h- and 24h treatment of H69 cells with G. cambogia extract in the presence of IL-6 cytokine produced concentration-dependent cytotoxic and pro-oxidant effects similar to that highlighted in normal conditions. Conversely, when the cells were challenged with IL-6 for 24 h and then treated with the extract in the absence of presence of IL-6, both cytotoxicity and oxidative stress were found increased by about 20-40% with respect to the noninflammatory conditions. Accordingly, the other assessed cell parameters were affected by treatments. Conclusion. Overall, our results showed that pre-existing inflammatory conditions may affect enhance the safety of G. cambogia, leading to increased cytotoxicity and impaired cytoprotective factors. These effects strengthen the need to carefully characterize the toxicity profile of botanicals in more susceptible people in order to prevent any adverse effects. References [1] Anilkumar et al. Biofactors 2023,49:584-599. [2] Crescioli et al. Intern Emerg Med. 2018,13:857-872. [3] Andueza et al. Nutrients 2021,13:450. [4] Di Giacomo et al. Antioxidants (Basel). 2023,12:1771. [5] Lumeng et al. J Clin Invest 2011, 121,2111–2117. [6] Han et al. PNAS 2020,117, 2751–2760.