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Spotlight Commentary: Why we need to pay attention to toxicity associated with herbal medicines

Nowadays, the popularity of medicinal herbs (MHs) and other natural products has increased dramatically worldwide. Consumers may use MHs as an alternative or complementary medicine to conventional drugs. Recently, we read two articles published in the British Journal of Clinical Pharmacology (BJCP) describing drug-induced liver injury (DILI) resulting in toxicity from the concomitant use of conventional drugs and MHs. The first article describes a patient treated with oral crizotinib who developed signs of liver distress. At that time, the patient presented with dramatically elevated levels of alanine aminotransferase (20 × ULN). Histological lesions suggested acute drug-induced hepatitis. In addition to crizotinib, the patient had consumed large quantities of hot water with honey, lemon juice and grated ginger roots (Zingiber officinale) for non-medical purposes. A detailed analysis of potential herb–drug interaction (HDI) revealed that ginger inhibits the activity of CYP3A4, CYP2C9 and P-gp enzymes, enzymes responsible for crizotinib metabolism. Elevated trough concentrations of crizotinib strengthen the opinion that a ginger–crizotinib drug interaction resulted in a potentiation of the crizotinib hepatotoxicity. The second case outlining a potential HDI was reported by Laube and Liu. An elderly patient presented with DILI after a long history of using atorvastatin. The patient used a dietary supplement containing Siberian ginseng (Eleuthero, Eleutherococcus senticosus (Rupr. & Maxim.)) and silymarin, a bioactive compound found in milk thistle (Silybum marianum (L.) Gaertn.), one week before elevated levels of aminotransferases were noticed (12–17 ULN). The authors proposed that ‘ginseng’ induced DILI via inhibition of CYP3A4, the enzyme responsible for atorvastatin metabolism. Eleuthero belongs to the same Parax genus as American ginseng (Panax quinquefolius) or Chinese ginseng (Panax ginseng) but possesses different bioactive constituents and has no effect on CYP3A4. Therefore, it should not interact with atorvastatin metabolism. It is possible that concomitant use of Eleuthero and/or milk thistle with other medications taken by the patient was responsible for the observed DILI. Another case of a potential HDI was described for a patient concomitantly using erlotinib with hibiscus (Hibiscus sabdariffa) tea, known for its anti-inflammatory and anti-tumour properties. The patient developed cutaneous lesions shortly after drinking the hibiscus tea. Discontinuation of the tea led to the rapid improvement of the cutaneous lesions. The analysis of potential HDI demonstrated that hibiscus inhibits CYP3A4 and CYP1A2, two enzymes responsible for erlotinib metabolism. In the case reports described above, patients self-prescribed MHs. Self-administered MHs like cassia (Cinnamomum cassia), chaparral (Larrea tridentate), gotu kola (Centella asiatica), comfrey (Symphytum officinale) and saw palmetto (Serenoa repens) are also capable of promoting liver toxicity. Numerous reports describe MH-associated nephrotoxicity. These MHs includeTaxus celebica, Tripterygium regelii, Clematis chinensis, Cassia obtusifolia, Gardenia jasminoides, Croton caudatus, Stephania tetrandra, Strychnos nux-vomica and many others. Aristolochic acid and the nephrotoxic alkaloids derived from these plants are often implicated as constituents that cause kidney damage. Chinese Traditional Medicine is often used as complementary or supportive medicine for the treatment of oncological patients. It has been reported that these MHs, as well as dietary supplements, are responsible for 26.8% of DILI hospitalizations, but it is not clear how many of these patients self-prescribed MHs. So and colleagues reported that their preliminary data indicate that 25% of patients with solid tumours were prescribed Chinese Traditional Medicines in [Correction added on 16 September 2020, after first online publication: Article title has been corrected in this online issue version.] Received: 21 April 2020 Accepted: 22 April 2020