Toxicological risk assessment of Aristolochia species. Johanna Michl

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1 Toxicological risk assessment of Aristolochia species Johanna Michl

2 Aristolochia Large plant genus of the family Aristolochiaceae Common names: birthwort, pipevines, Duchtman s pipes Occur on all continents Aristolochia manshuriensis Aristolochia maxima Aristolochia clematitis Aristolochia gigantea Aristolochia tricaudata Aristolochia serpentaria Aristolochia californica

Aristolochic acid nephropathy Progressive form of renal fibrosis 1 Initially reported in more

has been replaced with Aristolochia fangchi Aristolochia contains carcinogenic and mutagenic

the UK) 2 Aristolochia clematitis could be responsible for the so-called Balkan-endemic

3 Aristolochic acid nephropathy Progressive form of renal fibrosis 1 Initially reported in more than 100 Belgian patients after the intake of slimming pills Chinese herb Stephania tetrandra has been replaced with Aristolochia fangchi Aristolochia contains carcinogenic and mutagenic aristolochic acids 1 as well as aristolactams AAN cases observed all over the world (including the UK) 2 Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy 3 1 Nortier et al. (2000) NEJM 2 Debelle et al. (2008) Kidney Int 3 Grollman et al. (2007) PNAS

Traditional Chinese Medicine Pin Yin name plant part species uses guang fang ji root Aristolochia fangchi

trilobus diuretic, gonorrhea guan mu tong stem Aristolochia manshuriensis diuretic, anti-inflammatory chuan mu tong

debilis anti-tussive, anti-astmathic tian xian teng herb Aristolochia contorta or A.

4 Traditional Chinese Medicine Pin Yin name plant part species uses guang fang ji root Aristolochia fangchi anti-rheumatic and diuretic han fang ji root Stephania tetrandra anti-asthmatic, diuretic mu fang ji root Cocculus trilobus diuretic, gonorrhea guan mu tong stem Aristolochia manshuriensis diuretic, anti-inflammatory chuan mu tong root Clematis armandii or C. montana diuretic, anti-inflammatory ma dou ling fruit Aristolochia contorta or A. debilis anti-tussive, anti-astmathic tian xian teng herb Aristolochia contorta or A. debilis diuretic, anti-rheumatic qing mu xiang root Aristolochia debilis pain relief Wu et al. (2007) Phytomedicine Aristolochia manshuriensis Stephania tetrandra Clematis vitalba

dermatology parasitology central nervous system Heinrich et al.

5 Medical uses veterinary uses endocrinology cardiovascular musculosceletal respiratory Aristolochia repens miscellaneous gastrointestinal bites and poison gyneacology nephrology infectious diseases dermatology parasitology central nervous system Heinrich et al. (2009 ) J Ethnopharmacol Aristolochia pilosa Aristolochia species are used all over the world and for most species their chemistry is not known.

6 Aims Chemical characterization of medicinally used Aristolochia species Identification and quantification of all aristolochic acid and aristolactams present Toxicological screening of Aristolochia extracts Comparison of toxicological properties of aristolochic acid analogues Comparative risk assessment of Aristolochia species

7 Metabolomics The systematic study of the unique chemical fingerprints that specific cellular processes leave behind. Separation Liquid chromatography Capillary electrophoresis Gas chromatography Structure elucidation NMR QTOF Orbitrap UV Quantification relative absolute Chemistry Informatics Biology Plants Microbes Animal organs unsupervised PCA ICA SOM HCA supervised PLS PLS-DA OPLS SVM AAN

8 Metabolomics The systematic study of the unique chemical fingerprints that specific cellular processes leave behind. Separation Liquid chromatography Capillary electrophoresis Gas chromatography Structure elucidation NMR QTOF Orbitrap UV Quantification relative absolute Chemistry Informatics Biology Plants Microbes Animal organs unsupervised PCA ICA SOM HCA supervised PLS PLS-DA OPLS SVM AAN

Metabolomics 1 H-Nuclear magnetic resonance (NMR)

samples Primary and secondary metabolites Liquid

compounds and measures their mass spectra Mainly

9 Metabolomics 1 H-Nuclear magnetic resonance (NMR) Measures properties of all protons present in the samples Primary and secondary metabolites Liquid chromatography mass spectrometry (LC-MS) Separates compounds and measures their mass spectra Mainly secondary metabolites Great for identification of compounds

10 Workflow 50 mg dried plant material +1 ml 70% MeOH filtering NMR +700 μl D 2 O + MeOD drying 700 μl Quantification of AA I, AA II, AA C and AL I Metabolite identification Multivariate statistics LC-MS

11 Results Aristolochia gigantea (leaf) AA D AA C glycoside AA II AL I glycoside AA D 7-OCH 3 AL IV AL I AA D glycoside AA I AA C AA II AA I Asarum heterotropoides (flower) AA I Aristolochia manshuriensis (stem) Aristolochia clematitis (leaf)

12 Future work LC-MS and NMR analysis of Aristolochia species Data processing Metabolite identification Toxicological screening of all extracts Further pharmacological tests on selected extracts and pure compounds Botanical fieldwork in India/Bangladesh

13 Acknowledgments Prof. Michael Heinrich (SOP - currently Southern Cross University) Dr. Martin Ingrouille (Birkbeck College) Prof. Monique Simmonds (Royal Botanic Gardens, Kew - SOP) The Centre for Pharmacognosy and Phythotherapy (SOP): Tony Booker, Amaka Izuka, Michelle Viteri, Rocio Alcaron, Ines Rocha, Hannah Jennings, Ivan Casselman, Nisarat Siriwantameton, Dominik Witzigmann, Giorgos Liappas Jodrell Laboratories (Kew): Geoffrey Kite, Elaine Porter, Christine Leon, Tetsuo Kokubun TU Dresden: Stefan Wanke, Sarah Wagner, Oliver Zierau London International Development Centre

WORKING PARTY ON HERBAL MEDICINAL PRODUCTS POSITION PAPER ON THE RISKS ASSOCIATED WITH THE USE OF HERBAL PRODUCTS CONTAINING ARISTOLOCHIA SPECIES

The European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use 31 October 2000 EMEA/HMPWP/23/00 WORKING PARTY ON HERBAL MEDICINAL PRODUCTS POSITION PAPER ON THE RISKS