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Mycotoxins are frequent toxic contaminants in foods and beverages, causing a significant health threat. Interactions of mycotoxins with biotransformation enzymes (e.g., cytochrome P450 enzymes, sulfotransferases, and uridine 5′-diphospho-glucuronosyltransferases) may be important due to their possible detoxification or toxic activation during enzymatic processes. Furthermore, mycotoxin-induced enzyme inhibition may affect the biotransformation of other molecules. A recent study described the strong inhibitory effects of alternariol and alternariol-9-methylether on the xanthine oxidase (XO) enzyme. Therefore, we aimed to test the impacts of 31 mycotoxins (including the masked/modified derivatives of alternariol and alternariol-9-methylether) on XO-catalyzed uric acid formation. Besides the in vitro enzyme incubation assays, mycotoxin depletion experiments and modeling studies were performed. Among the mycotoxins tested, alternariol, alternariol-3-sulfate, and α-zearalenol showed moderate inhibitory actions on the enzyme, representing more than tenfold weaker impacts compared with the positive control inhibitor allopurinol. In mycotoxin depletion assays, XO did not affect the concentrations of alternariol, alternariol-3-sulfate, and α-zearalenol in the incubates; thus, these compounds are inhibitors but not substrates of the enzyme. Experimental data and modeling studies suggest the reversible, allosteric inhibition of XO by these three mycotoxins. Our results help the better understanding of the toxicokinetic interactions of mycotoxins.

Introduction: The public health threat of substandard and falsified medicines has been well known in the last two decades, and several studies focusing on the identification of products affected and preventing consumption have been published. However, the number of these products reaching patients and causing health consequences and adverse drug reactions is not a well-researched area.Objectives: Our aim was to identify and describe the characteristics of cases that are related to adverse drug reactions potentially originating from counterfeit medication using publicly available pharmacovigilance data.Methods: A descriptive study was performed based on pharmacovigilance data retrieved from Individual Case Safety Reports (ICSRs) identified in the European Medicines Agency’s EudraVigilance and FDA Adverse Event Reporting System (FAERS) databases in April 2022 using selected MedDRA preferred terms: counterfeit product administered, product counterfeit, product label counterfeit, product packaging counterfeit, suspected counterfeit product, adulterated product, product tampering, and suspected product tampering. ICSRs were analyzed by age and gender, by year of reporting, region of origin, reporter’s profession, and severity of the outcome. The disproportionality method was used to calculate pharmacovigilance signal measures.Results: A total of 5,253 cases in the FAERS and 1,049 cases in the EudraVigilance database were identified, generally affecting middle-aged men with a mean age of 51.055 (±19.62) in the FAERS and 64.18% of the cases between 18 and 65 years, while the male to female ratios were 1.18 and 1.5. In the FAERS database, we identified 138 signals with 95% confidence interval including sildenafil (n = 314; PRR, 12.99; ROR, 13.04; RRR, 11.97), tadalafil (n = 200; PRR, 11.51; ROR, 11.55; RRR, 10.94), and oxycodone (n = 190; PRR, 2.47; ROR, 2.14; RRR, 2.47). While in the EV data 31, led by vardenafil (n = 16, PRR = 167.19; 101.71–274.84; 95% CI, RRR = 164.66; 100.17–270.66; 95% CI, ROR = 169.47; 103.09–278.60; 95% CI, p < 0.001), entecavir (n = 46, PRR = 161.26, RRR = 154.24, ROR = 163.32, p < 0.001), and tenofovir (n = 20, PRR = 142.10, RRR = 139.42, ROR = 143.74, p < 0.001).Conclusion: The application of pharmacovigilance datasets to identify potential counterfeit medicine ADRs can be a valuable tool in recognition of potential risk groups of consumers and the affected active pharmaceutical ingredients and products. However, the further development and standardization of ADR reporting, pharmacovigilance database analysis, and prospective and real-time collection of potential patients with health consequences are warranted in the future.