Comprehensive investigation and risk study on pyrrolizidine alkaloid contamination in Chinese retail honey

He, Yisheng; Zhu, Lin; Ma, Jiang; Wong, Lailai; Zhao, Zhongzhen; Yang, Yong; Fu, Peter P.; Lin, Ge

doi:10.1016/j.envpol.2020.115542

Cited by 31 publications

(14 citation statements)

References 36 publications

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“…Humans are frequently exposed to dietary PAs via the intake of PA-contaminated foods such as honey and milk, which are derived from the carry-over PAs in PA-exposed livestock, and this type of intermittent, low-level dietary exposure is likely to have occurred in the past and seems increasingly to continue to the present day to varying degrees in many regions worldwide 5 , 35 . Delineation of the chronic toxicological behavior of PAs is essential for risk management of these widely available phytotoxins.…”

Section: Discussionmentioning

confidence: 99%

The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

Fan

et al. 2021

Acta Pharmaceutica Sinica B

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Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut–liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

Fan

et al. 2021

Acta Pharmaceutica Sinica B

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“…Apart from causing acute liver injury, PAs are also documented carcinogens in experimental animals . Tumorigenic risks of PAs are more prominent than acute intoxication, because humans are more commonly exposed to low levels of PAs via PA-contaminated food products, , which would not cause acute hepatic symptoms. However, due to the lack of human epidemiological data, the World Health Organization has categorized PAs as Group 2B carcinogens (possible human carcinogens) .…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2021

Environ. Sci. Technol. Lett.

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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.

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“…More than 660 potentially poisonous PAs and PA N -oxides have been identified in over 6000 plants (Fu et al 2004 ; Yang et al 2017 ). Humans are readily exposed to toxic PAs through the consumption of PA-producing plants used as herbal medicines, herbal teas, and dietary supplements (Edgar et al 2015 ; Kakar et al 2010 ), and PA-contaminated staple foods such as grains, milk, tea, and honey (Edgar et al 1999 ; He et al 2020 ; Kempf et al 2010 ; Zhu et al 2018 ). In humans, ingestion of PAs and PA N -oxides often results in liver injury, particularly the severe PA-induced liver injury (PA-ILI) can cause hepatic sinusoidal obstruction syndrome (HSOS) with typical symptoms of hepatomegaly, jaundice, and ascites (Chojkier 2003 ; DeLeve et al 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Developing urinary pyrrole–amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human

Zhu

Zhang

et al. 2021

Arch Toxicol

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Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Currently, a definitive diagnostic method for PA-induced liver injury (PA-ILI) is lacking. In the present study, using a newly developed analytical method, we identified four pyrrole-amino acid adducts (PAAAs), namely pyrrole-7-cysteine, pyrrole-9-cysteine, pyrrole-9-histidine, and pyrrole-7-acetylcysteine, which are generated from reactive pyrrolic metabolites of PAs, in the urine of PA-treated male Sprague Dawley rats and PA-ILI patients. The elimination profiles, abundance, and persistence of PAAAs were systematically investigated first in PA-treated rat models via oral administration of retrorsine at a single dose of 40 mg/kg and multiple doses of 5 mg/kg/day for 14 consecutive days, confirming that these urinary excreted PAAAs were derived specifically from PA exposure. Moreover, we determined that these PAAAs were detected in ~ 82% (129/158) of urine samples collected from ~ 91% (58/64) of PA-ILI patients with pyrrole-7-cysteine and pyrrole-9-histidine detectable in urine samples collected at 3 months or longer times after hospital admission, indicating adequate persistence time for use as a clinical test. As direct evidence of PA exposure, we propose that PAAAs can be used as a biomarker of PA exposure and the measurement of urinary PAAAs could be used as a non-invasive test assisting the definitive diagnosis of PA-ILI in patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03129-6.

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Comprehensive investigation and risk study on pyrrolizidine alkaloid contamination in Chinese retail honey

Cited by 31 publications

References 36 publications

The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

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

Developing urinary pyrrole–amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human

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