toxins Review Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids Mengbi Yang, Xiaoyu Ji and Zhong Zuo * School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China; [email protected] (M.Y.); [email protected] (X.J.) * Correspondence: [email protected]; Tel.: +852-3943-6832 Received: 17 August 2018; Accepted: 14 September 2018; Published: 26 September 2018 Abstract: The processed lateral root of Aconitum carmichaelii Deb (Aconiti Radix lateralis praeparata or Fuzi) is a potent traditional herbal medicine extensively used in treatment of cardiovascular diseases, rheumatism arthritis, and bronchitis in many Asian countries. Although Fuzi has promising therapeutic effects, its toxicities are frequently observed. Three main C19-diester-diterpenoid alkaloids (DDAs) are believed to be the principal toxins of the herb. Although toxicokinetic profiles of the toxic DDAs have already been examined in several studies, they have seldom been correlated with the toxicities of Fuzi. The current article aimed to investigate the relationship between the up-to-date toxicokinetic data of the toxic DDAs and the existing evidence of the toxic effects of Fuzi. Relationships between the cardiac toxicity and the plasma and heart concentration of DDAs in mice and rats were established. Based on our findings, clinical monitoring of the plasma concentrations of DDAs of Fuzi is recommended to prevent potential cardiac toxicities. Additionally, caution with respect to potential hepatic and renal toxicity induced by Fuzi should be exercised. In addition, further analyses focusing on the preclinical tissue distribution profile of DDAs and on the long-term toxicokinetic-toxicity correlation of DDAs are warranted for a better understanding of the toxic mechanisms and safer use of Fuzi. Keywords: Aconiti Radix lateralis praeparata; Fuzi; diester-diterpenoid alkaloids; toxicokinetics; herb safety; herb-induced toxicity Key Contribution: The current review investigates the relationship between the up-to-date toxicokinetic data of the toxic DDAs and the existing evidence of the toxic effects of Fuzi. Based on our findings, clinical monitoring of the plasma concentrations of DDAs of Fuzi is recommended to prevent potential cardiac toxicities. Additionally, caution with respect to potential hepatic and renal toxicity induced by Fuzi should be exercised. 1. Introduction Aconitum carmichaelii Deb is a famous traditional Chinese medicinal herb. Its processed lateral root (Aconiti Radix lateralis praeparata or Fuzi) is extensively used in the treatments of cardiovascular diseases, rheumatism arthritis, bronchitis, pains, and hypothyroidism. In clinical practice in China, Fuzi is the constituent of more than 60 well-known traditional Chinese formulae frequently used [1]. A. carmichaeli belongs to the genus of Aconitum, which consists of over 300 species distributed in the temperate regions of the north hemisphere and 211 species in China. In total, 76 species of Aconitum have been used as herbal medicine or ethnomedicine in countries such as Indian, Vietnamese, Korean, Japanese, and China [1–3]. Toxins 2018, 10, 391; doi:10.3390/toxins10100391 www.mdpi.com/journal/toxins Toxins 2018, 10, x FOR PEER REVIEW 2 of 19 speciesToxins 2018 of, Aconitum10, 391 have been used as herbal medicine or ethnomedicine in countries such as Indian,2 of 18 Vietnamese, Korean, Japanese, and China [1–3]. Although Fuzi has demonstrated promising therapeutic effects, its potential cardiotoxicity and neurotoxicityAlthough are Fuzi frequently has demonstrated observed [2]. promising Thus, the therapeutic clinical dosage effects, of Fuzi its potential is regulated cardiotoxicity in many Asian and countriesneurotoxicity such areas Japan, frequently China, observed and Korea [2]. [4]. Thus, The theclinical clinical recommended dosage of Fuzidaily is dose regulated of Fuzi in is many3–15 g/personAsian countries according such to asthe Japan, Chinese China, Pharmacopoeia and Korea [[5].4]. TheHowever, clinical the recommended actual clinical daily dose dose of Fuzi of Fuzican sometimesis 3–15 g/person be much according higher, leading to the Chinese to numerous Pharmacopoeia intoxication [5]. cases. However, From the2001 actual to 2010, clinical there dose were of aboutFuzi can 5000 sometimes cases of beaconite much poisoning higher, leading reported to numerous worldwide intoxication including cases.China, From Japan, 2001 Germany, to 2010, thereand otherwere aboutcountries 5000 [2,4,6–13]. cases of aconite Between poisoning 2012 and reported 2017 in worldwide Hong Kong, including more China,than 41 Japan, aconite Germany, poisoning and casesother were countries reported. [2,4,6– 13In ].Mainland Between 2012China, and at 2017 least in 40 Hong single Kong, or moremulti-person than 41 aconitecases of poisoning fatal aconite cases poisoningwere reported. were Inreported Mainland between China, 2003 at least and 402015, single involv or multi-personing 53 victims cases [6]. It of was fatal found aconite that poisoning aconite poisoningwere reported was betweenmainly due 2003 to and improper 2015, involving self-prescription, 53 victims mistaken [6]. It was ingestion found that of aconiteA. carmichaeli poisoning for ediblewas mainly plants, due and to contamination improper self-prescription, of A. carmichaeli mistaken in other medicinal ingestion ofherbsA.carmichaeli [1,6–8]. In addition,for edible aconite plants, poisoningand contamination has been offoundA. carmichaeli in suicidein and other homicide medicinal cases herbs [1,10–13]. [1,6–8]. In addition, aconite poisoning has beenThe found principal in suicide bioactive and homicide ingredients cases in aconite [1,10–13 roots]. are the C19-diterpenoid alkaloids [1,14]. Three main Thediester-diterpenoid principal bioactive alkaloids ingredients (DDAs), in aconite namely, roots aconitine are the (AC), C19-diterpenoid mesaconitine alkaloids (MA), [1and,14]. hypaconitineThree main diester-diterpenoid (HA), are believed alkaloidsto be the (DDAs),major toxic namely, components aconitine of (AC),the herb mesaconitine (Figure 1) (MA),[1,14–16]. and Thehypaconitine toxicity of (HA),AC has are been believed elaborated to be since the majorthe 1980 toxics [1,2,14,17], components whilst of the the toxicokinetics herb (Figure1 of)[ the1,14 three–16]. mainThe toxicitytoxic DDAs of AC were has beenlargely elaborated unknown since until the the 1980s last decade. [1,2,14, 17Since], whilst the absorption, the toxicokinetics distribution, of the metabolism,three main toxic and DDAsexcretion were properties largely unknown of these untiltoxic the ingredients last decade. are Since expected the absorption, to determine distribution, the safe dosemetabolism, of the herb, and understanding excretion properties of the oftoxicity these an toxicd toxicokinetic ingredients properties are expected of the to determine main toxic the DDAs safe isdose essential of the for herb, the understanding dosage regimen of and the toxicityrisk contro andl of toxicokinetic Fuzi. The pharmacokinetics properties of the mainof Fuzi toxic and DDAs their biologicalis essential mechanisms for the dosage have regimen been well-delinea and risk controlted and of Fuzi.reviewed The pharmacokinetics[18]. Based on the of previous Fuzi and publicationstheir biological on mechanismstoxicity and havetoxicokinetics been well-delineated of Fuzi and and its reviewedDDAs, our [18 ].current Based review on the previousaims to investigatepublications the on toxicity–toxicokinetic toxicity and toxicokinetics relationship of Fuzi andof Fuzi its DDAs, and its our main current toxic reviewDDAs,aims which to may investigate serve asthe references toxicity–toxicokinetic for further clinical relationship safety ofassessment. Fuzi and its main toxic DDAs, which may serve as references for furtherThe following clinical safetydatabases assessment. were searched to identify relevant literatures in both English and Chinese:The Pubmed following (from databases 1959 to were Aug searched 2018) and to identify China National relevant literaturesKnowledge in Infrastructure both English and (from Chinese: 1994 toPubmed Aug 2018). (from Both 1959 toLatin Aug and 2018) Chinese and China pinyin National terms Knowledgeincluding “Fuzi,” Infrastructure “Lateral (from roots 1994 of toAconitum August carmichaelii2018). 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