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The Development of a Database for Herbal and Dietary Supplement Induced Liver Toxicity

Zhu, Jieqiang, Seo, Ji-Eun, Wang, Sanlong, Ashby, Kristin, Ballard, Rodney, Yu, Dianke, Ning, Baitang, Agarwal, Rajiv, Borlak, Jürgen, Tong, Weida, Chen, Minjun·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19102955PMC PMC6213387
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Abstract

The growing use of herbal dietary supplements (HDS) in the United States provides compelling evidence for risk of herbal-induced liver injury (HILI). Information on HDS products was retrieved from MedlinePlus of the U.S. National Library of Medicine and the herbal monograph of the European Medicines Agency. The hepatotoxic potential of HDS was ascertained by considering published case reports. Other relevant data were collected from governmental documents, public databases, web sources, and the literature. We collected information for 296 unique HDS products. Evidence of hepatotoxicity was reported for 67, that is 1 in 5, of these HDS products. The database revealed an apparent gender preponderance with women representing 61% of HILI cases. Culprit hepatotoxic HDS were mostly used for weight control, followed by pain and inflammation, mental stress, and mood disorders. Commonly discussed mechanistic events associated with HILI are reactive metabolites and oxidative stress, mitochondrial injury, as well as inhibition of transporters. HDS–drug interactions, causing both synergistic and antagonizing effects of drugs, were also reported for certain HDS. The database contains information for nearly 300 commonly used HDS products to provide a single-entry point for better comprehension of their impact on public health.

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Figure 1 Increases in herbal dietary supplement (HDS) sales and in publications reporting HDS hepatotoxicity. Total sales for HDS have steadily increased in the U.S. market. With increasing HDS use, publications on liver injury due to HDS also have increased accordingly. The sources of HDS sales and publications are from the market reports in HerbalGram (http://abc.herbalgram.org/site/PageServer) and PubMed (accessed on 1 September 2017), respectively.
Figure 1 Increases in herbal dietary supplement (HDS) sales and in publications reporting HDS hepatotoxicity. Total sales for HDS have steadily increased in the U.S. market. With increasing HDS use, publications on liver injury due to HDS also have increased accordingly. The sources of HDS sales and publications are from the market reports in HerbalGram (http://abc.herbalgram.org/site/PageServer) and PubMed (accessed on 1 September 2017), respectively.CC BY · PubMed Central
Figure 2 Data sources for the collection of 296 herbal and dietary supplements (HDS) evaluated for hepatotoxicity.
Figure 2 Data sources for the collection of 296 herbal and dietary supplements (HDS) evaluated for hepatotoxicity.CC BY · PubMed Central
Figure 3 HDS use and associated hepatotoxicity. (A) The distribution of HDS hepatotoxicity. An HDS was evidenced as hepatotoxic when it was identified as the culprit cause of the injury in at least one qualified case report. (B) The distribution of human use of HDS with and without evidence of hepatotoxicity.
Figure 3 HDS use and associated hepatotoxicity. (A) The distribution of HDS hepatotoxicity. An HDS was evidenced as hepatotoxic when it was identified as the culprit cause of the injury in at least one qualified case report. (B) The distribution of human use of HDS with and without evidence of hepatotoxicity.CC BY · PubMed Central
Figure 4 Potential mechanisms of HDS-induced liver injury. Most HDS hepatotoxicity develops through direct hepatocyte toxicity or by triggering an immune response. Toxic ingredients or their reactive metabolites cause direct hepatocyte toxicity through various mechanisms, such as oxidative stress, endoplasmic reticulum (ER) stress, DNA damage, toxic bile acids accumulation, and mitochondrial dysfunction, consequently leading to cell apoptosis or necrosis. Another important mechanism resulting in cell damage occurs when either toxic HDS ingredients, reactive metabolites, or danger damage-associated molecular patterns (DAMPs) released by stressed hepatocytes trigger an immune response. The exact mechanism leading to HDS-hepatotoxicity is still under investigation and other pathways may be involved.
Figure 4 Potential mechanisms of HDS-induced liver injury. Most HDS hepatotoxicity develops through direct hepatocyte toxicity or by triggering an immune response. Toxic ingredients or their reactive metabolites cause direct hepatocyte toxicity through various mechanisms, such as oxidative stress, endoplasmic reticulum (ER) stress, DNA damage, toxic bile acids accumulation, and mitochondrial dysfunction, consequently leading to cell apoptosis or necrosis. Another important mechanism resulting in cell damage occurs when either toxic HDS ingredients, reactive metabolites, or danger damage-associated molecular patterns (DAMPs) released by stressed hepatocytes trigger an immune response. The exact mechanism leading to HDS-hepatotoxicity is still under investigation and other pathways may be involved.CC BY · PubMed Central
Figure 5 The screenshot of the Herbal and Dietary Supplements Hepatotoxicity Database (currently only for FDA users).
Figure 5 The screenshot of the Herbal and Dietary Supplements Hepatotoxicity Database (currently only for FDA users).CC BY · PubMed Central

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Citations

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Metadata

Authors
Zhu, J., Seo, J.-E., Wang, S., Ashby, K., Ballard, R., Yu, D., Ning, B., Agarwal, R., Borlak, J., Tong, W., & Chen, M.
Affiliations
  • Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
  • Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
  • Center of Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany
ORCID
Borlak, Jürgen
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-09-28
Volume
19
Issue
10
Pages
2955
ISSN
1422-0067
DOI
10.3390/ijms19102955
PMC
PMC6213387
Cited by
29
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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