Potential Hepatotoxins Found in Herbal Medicinal Products: A Systematic Review

Abstract

The risk of liver injury associated with the use of herbal medicinal products (HMPs) is well known among physicians caring for patients under a HMP therapy, as documented in case reports or case series and evidenced by using the Roussel Uclaf Causality Assessment Method (RUCAM) to verify a causal relationship. In many cases, however, the quality of HMPs has rarely been considered regarding potential culprits such as contaminants and toxins possibly incriminated as causes for the liver injury. This review aims to comprehensively assemble details of tentative hepatotoxic contaminants and toxins found in HMPs. Based on the origin, harmful agents may be divided according two main sources, namely the phyto-hepatotoxin and the nonphyto-hepatotoxin groups. More specifically, phyto-hepatotoxins are phytochemicals or their metabolites naturally produced by plants or internally in response to plant stress conditions. In contrast, nonphyto-hepatotoxic elements may include contaminants or adulterants occurring during collection, processing and production, are the result of accumulation of toxic heavy metals by the plant itself due to soil pollutions, or represent mycotoxins, herbicidal and pesticidal residues. The phyto-hepatotoxins detected in HMPs are classified into eight major groups consisting of volatile compounds, phytotoxic proteins, glycosides, terpenoid lactones, terpenoids, alkaloids, anthraquinones, and phenolic acids. Nonphyto-hepatotoxins including metals, mycotoxins, and pesticidal and herbicidal residues and tentative mechanisms of toxicity are discussed. In conclusion, although a variety of potential toxic substances may enter the human body through HMP use, the ability of these toxins to trigger human liver injury remains largely unclear.

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

“…Modern and traditional herbal medicines commonly use selected herbal products as medicinal plants, some of which contain PAs, to treat patients with less serious ailments [ 22 ], although the efficacy for most indications is insufficiently reported due to the lack of positive results based on randomized controlled trials (RCTs) [ 46 , 47 ]. HILI, in the context of herbal medicine, remains a particular challenge as shown by multiple published liver injury cases [ 8 , 9 , 10 , 11 , 19 ]. Yet, HILI by TCM was rarely observed in a prospective study in Germany, due to having checked the quality of the herbal TCM medicines prior to use [ 48 ].…”

“…Patients with acute or chronic liver diseases represent a clinical challenge if toxins are suspected, as possible causes are diverse, such as plant-derived 1,2-unsaturated pyrrolizidine alkaloids (PAs) [ 1 , 2 , 3 , 4 , 5 , 6 ], various other phytochemicals [ 7 , 8 , 9 , 10 , 11 ], ethanol [ 12 , 13 , 14 , 15 ], conventional drugs [ 16 , 17 , 18 , 19 ], or industrial aliphatic halogenated hydrocarbons like carbon tetrachloride [ 20 ]. Most of these toxins share the common feature of metabolic activation as a prerequisite for their liver-injurious potential, but they may differ regarding their chemical structures, types of liver injury, and typical clinical features.…”

“…At recommended daily doses or overdosed, drugs may lead to drug-induced liver injury (DILI) with the risk of acute liver failure, requiring liver transplantation [ 16 , 17 , 18 , 19 ]. Finally, herbal products used as prescribed or over-the-counter medicines are causes of rare but potentially life-threatening herb-induced liver injury (HILI) [ 7 , 8 , 9 , 10 , 11 ]. Among the plants leading to most severe liver injury are those with 1,2-unsaturated PAs as ingredients.…”

Roles of SET7/9 and LSD1 in the Pathogenesis of Arsenic-induced Hepatocyte Apoptosis

“…28 Since ancient times, raw plants as well as refined plant products have been in common use, including as traditional Chinese medicine, Ayurveda in India, Kampo in Japan, traditional Korean medicine, and Unani in old Greece, all of which have well known associations with increased risk of liver damage. 29 In many countries, rice grains and complementary medicines are important sources of arsenic consumption. 30 Ayurvedic is an arsenic-containing compound, which is currently in use in India to control blood counts of patients with hematological malignancies.…”

DataSheet2.PDF

“…Herbs contain thousands of chemical compounds. Some compounds have been proved to be hepatotoxins including volatile compounds, phytotoxic proteins, glycosides, terpenoid lactones, terpenoids, alkaloids, anthraquinones, and phenolic acids (Quan et al, 2020). However, it is unclear that if the proper application of formulas containing these medicinals contributes to liver injury or not.…”