Synergistic Safety Enhancement of Gadodiamide in Combination With Fulvic/Humic Acids and Vitamin C in Hek-293 Cells and Wistar Rats Publisher



Zonoubi N¹ ; Mehrizi TZ² ; Shafiee Ardestani M¹ Show Affiliations
Source: Toxicological and Environmental Chemistry Published:2025

Abstract

Gadolinium-based contrast agents (GBCAs) are widely used in imaging diagnostics, but their nephrotoxicity remains an issue. This study evaluates the potential of metal chelators, that is, fulvic acid (FA) and humic acid (HA), in combination with the antioxidant vitamin C, against neutralizing the toxic effect of gadodiamide (Omniscan). Different synergistic mixtures were formulated, and their patterns of toxicity were assessed by in vitro (on HEK-293 cells) and in vivo (on Wistar rats) tests. The MTT assay revealed that FA/HA alone, when co-treated with gadodiamide, did not differ significantly from gadodiamide treatment. Similarly, vitamin C alone offered a modest, but statistically insignificant, protective effect. However, the FA/HA + vitamin C combination significantly increased cell viability compared to both gadodiamide + FA/HA alone (p = 0.0005) and gadodiamide + vitamin C alone (p = 0.0256). FA/HA and vitamin C at 200 µg/mL were most effective in counteracting gadodiamide cytotoxicity. The annexin V-FITC/PI staining supported these findings. While FA/HA (200 µg/mL) with gadodiamide showed the highest rate of apoptosis, vitamin C inclusion significantly reduced apoptosis and achieved cell viability comparable to normal saline controls. Histopathological analysis of kidneys from Wistar rats treated with the optimized formulation (gadodiamide + FA/HA + vitamin C, 200 µg/mL) did not reveal significant pathological changes, while the use of gadodiamide alone produced apoptotic alterations. These results show that the co-administration of antioxidants and metal chelators with gadodiamide markedly decreases its nephrotoxicity in a concentration-dependent manner, offering a potential strategy for safer GBCA administration. © 2025 Informa UK Limited, trading as Taylor & Francis Group.