Blood Pyrrole–DNA Adducts Define the Early Tumorigenic Risk in Patients with Pyrrolizidine Alkaloid-Induced Liver Injury

Abstract

Pyrrolizidine alkaloids (PAs) are among the most common phytotoxins with emerging evidence to contaminate soil, water, and nearby plants. Humans are frequently exposed to PA-contaminated food products or PA-containing herbal remedies. The reactive metabolites of PAs rapidly alkylate DNA to form pyrrole–DNA adducts (PDAs) and seed a population of mutations that initiate tumorigenesis in experimental models. However, the clinical evidence of PA-induced initial DNA damage is absent. This study developed a liquid biopsy approach for detecting PDAs in blood to diagnose PA-induced genotoxicity. Blood DNA samples, extracted from PA-exposed rats, were reacted with silver nitrate to cleave the N-linkage between conjugated DNA bases and pyrrole. The released pyrrole was chemically derivatized to a stable product which was measured by liquid chromatography-tandem mass spectrometry. Using this method, PDAs were, for the first time, detected in blood samples from 18 patients with PA-induced liver injury. Notably, PDAs were detectable in patients’ blood samples collected one month after hospital admission, indicating adequate persistence of PDAs for use as a clinical biomarker of PA-induced genotoxicity. Our findings provide clinical indication of PA-induced genotoxicity, which warrants early detection of PDAs as an actionable approach for prevention of PA-associated carcinogenesis.

Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole–Protein Adducts

“…Increasing evidence suggests that PA exposure biomarkers, such as pyrrole-protein adducts, pyrrole-DNA adducts, and pyrrole-amino acid adducts, are specific and applicable diagnostic biomarkers. This evidence supports the causality assessment used in the updated RUCAM [27,[41][42][43]. Therefore, for future clinical diagnosis of suspected PA-induced HSOS cases, the RUCAM, the Nanjing criteria, and specific PA exposure biomarkers should be applied together to confirmatively diagnose PA-induced HSOS cases.…”

Application of Nanofibers in Virus and Bacteria Filtration

“…They reported that increase of electrospinning duration and thickness of the air filters enhanced coronavirus aerosol removal (99.9% and 99.1% for PVDF 30 and PVDF 20 , respectively), though there was a marginal decrease of the pore size of PVDF 30 compared to PVDF 20 . Polyelectrolyte coating did not promote electrospun air filters for removing coronavirus aerosols, and the average filtration efficiency for PVDF 20 /PEI and PVDF 20 /PVPA was 99.1% and 95.7%, respectively [ 62 ]. Also, Shen et al a homogeneous electrospinning dope solution containing of polyvinylidene difluoride (PVDF) and a dye photosensitizer in N,N -dimethylformamide/acetone was electrospun onto one layer of polypropylene (PP) fabrics (basic protection face mask).…”

Liquorice Extract and 18β-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation

“…This injury is confirmatively diagnosed by blood pyrrole-protein adducts, which are specific diagnostic biomarkers, supporting the causality evaluation using the updated Roussel Uclaf Causality Assessment Method (RUCAM) ( Danan and Teschke, 2016 ; Teschke and Danan, 2020 ). Furthermore, our recent study discovered an unexpectedly extensive implication of PA exposure in patients with liver cancer, providing a clinical indication of PA-associated liver cancer ( He et al, 2021c ).…”