The importance of the phytocomplex in the safety assessment of red yeast rice and plants containing hydroxyanthracenes

The safety evaluation of botanical supplements requires a multidisciplinary approach that considers the phytocomplex as a whole, rather than focusing solely on isolated active constituents. This study, which reflects the approach of SIFITLab to botanicals under EFSA investigation, focuses on two representative cases: red yeast rice (RYR) and plants containing hydroxyanthracenes (HADs). For RYR, numerous samples with varying monacolin K (MK) content were analyzed via HPLC-DAD, revealing substantial variability not only in MK but also in secondary monacolins, triterpenes, and polyphenols. Enzymatic assays showed that the RYR phytocomplex exhibited superior HMG-CoA reductase inhibition compared to pure lovastatin (LOV), indicating possible synergistic effects. Moreover, in vitro testing on intestinal, hepatic, renal, and muscle cells demonstrated lower cytotoxicity of RYR compared to LOV. In muscle cells, qRT-PCR analyses confirmed a milder impact on the expression of genes related to damage, supporting a better safety profile [ 1 ]. In parallel, HAD-containing botanical extracts were compared to single HAD compounds in terms of stability, bioaccessibility, and intestinal toxicity. Simulated digestion and in silico modeling showed that HAD glycosides were stable but not absorbed, while aglycones exhibited limited bioaccessibility, highly dependent on the plant matrix. Importantly, whole extracts were far less cytotoxic than isolated HADs and did not affect oxidative or inflammatory markers in Caco-2 cells [ 2 ]. These results underline that the phytocomplex can significantly modulate both efficacy and safety. Future regulatory and scientific assessments should adopt phytocomplex-based evaluation strategies to ensure accurate and clinically relevant risk-benefit assessments of botanical preparations. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany