Metabolism, Genotoxicity, annd Carcinogenicity of Comfrey

REFERENCES

• Abbott , P. J. 1988 . Comfrey: Assessing the low-dose health risk . Med. J. Aust. , 149 : 678 – 682 .
   PubMed Web of Science ®Google Scholar
• Altamirano , J.C. , Gratz , S.R. and Wolnik , K.A. 2005 . Investigation of pyrrolizidine alkaloids and their N-oxides in commercial comfrey-containing products and botanical materials by liquid chromatography electrospray ionization mass spectrometry . J. Am. Off. Assoc. Chem. Int. , 88 : 406 – 412 .
   Google Scholar
• Bach , N. , Thung , S. N. and Schaffner , F. 1989 . Comfrey herb tea-induced hepatic veno-occlusive disease . Am. J. Med. , 87 : 97 – 99 .
   PubMed Web of Science ®Google Scholar
• Behninger , C. , Abel , G. , Roder , E. , Neuberger , V. and Goggelmann , W. 1989 . [Studies on the effect of an alkaloid extract of Symphytum officinale on human lymphocyte cultures] . Planta Med. , 55 : 518 – 522 .
   PubMedGoogle Scholar
• Betz , J. M. , Eppley , R. M. , Taylor , W. C. and Andrzejewski , D. 1994 . Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.) . J. Pharm. Sci. , 83 : 649 – 653 .
   PubMed Web of Science ®Google Scholar
• Bleakley , C. M. , McDonough , S. M. and MacAuley , D. C. 2008 . Some conservative strategies are effective when added to controlled mobilisation with external support after acute ankle sprain: A systematic review . Aust. J. Physiother. , 54 : 7 – 20 .
   PubMed Web of Science ®Google Scholar
• Brauchli , J. , Luthy , J. , Zweifel , U. and Schlatter , C. 1982 . Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats . Experientia , 38 : 1085 – 1087 .
   PubMedGoogle Scholar
• Chen , T. , Mei , N. and Fu , P. P. 2010 . Genotoxicity of pyrrolizidine alkaloids . J. Appl. Toxicol. , 30 : 183 – 196 .
   PubMed Web of Science ®Google Scholar
• Chou , M. W. and Fu , P. P. 2006 . Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids . Toxicol. Ind. Health , 22 : 321 – 327 .
   PubMed Web of Science ®Google Scholar
• Chou , M. W. , Jian , Y. , Williams , L. D. , Xia , Q. , Churchwell , M. , Doerge , D. R. and Fu , P. P. 2003a . Identification of DNA adducts derived from riddelliine, a carcinogenic pyrrolizidine alkaloid . Chem. Res. Toxicol. , 16 : 1130 – 1137 .
   PubMed Web of Science ®Google Scholar
• Chou , M. W. , Wang , Y. P. , Yan , J. , Yang , Y. C. , Beger , R. D. , Williams , L. D. , Doerge , D. R. and Fu , P. P. 2003b . Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine . Toxicol. Lett. , 145 : 239 – 247 .
   PubMed Web of Science ®Google Scholar
• Chou , M. W. , Yan , J. , Nichols , J. , Xia , Q. , Beland , F. A. , Chan , P. C. and Fu , P. P. 2003c . Correlation of DNA adduct formation and riddelliine-induced liver tumorigenesis in F344 rats and B6C3F(1) mice . Cancer Lett. , 193 : 119 – 125 .
   PubMed Web of Science ®Google Scholar
• Couet , C. E. , Crews , C. and Hanley , A. B. 1996 . Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . Nat. Toxins , 4 : 163 – 167 .
   PubMedGoogle Scholar
• Crews , C. , Startin , J. R. and Clarke , P. A. 1997 . Determination of pyrrolizidine alkaloids in honey from selected sites by solid phase extraction and HPLC-MS . Food Addit. Contam. , 4 : 419 – 428 .
   Google Scholar
• Deinzer , M. L. , Thomson , P. A. , Burgett , D. M. and Isaacson , D. L. 1977 . Pyrrolizidine alkaloids: Their occurrence in honey from tansy ragwort (Senecio jacobaea L.) . Science , 195 : 497 – 499 .
   PubMed Web of Science ®Google Scholar
• DeLeve , L. D. , Shulman , H. M. and McDonald , G. B. 2002 . Toxic injury to hepatic sinusoids: Sinusoidal obstruction syndrome (veno-occlusive disease) . Semin. Liver Dis. , 22 : 27 – 42 .
   PubMed Web of Science ®Google Scholar
• Dueker , S. R. , Lame , M. W. , Morin , D. , Wilson , D. W. and Segall , H. J. 1992 . Guinea pig and rat hepatic microsomal metabolism of monocrotaline . Drug Metab. Dispos. , 20 : 275 – 280 .
   PubMed Web of Science ®Google Scholar
• Edgar , J. A. , Roeder , E. and Molyneux , R. J. 2002 . Honey from plants containing pyrrolizidine alkaloids: A potential threat to health . J. Agric. Food Chem. , 50 : 2719 – 2730 .
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. 2001. FDA advises dietary supplement manufacturers to remove comfrey products from the market. USFDA, Center for Food Safety and Applied Nutrition http://www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.htm (http://www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.htm)
   Google Scholar
• Frei , H. , Luthy , J. , Brauchli , J. , Zweifel , U. , Wurgler , F. E. and Schlatter , C. 1992 . Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster . Chem. Biol. Interact. , 83 : 1 – 22 .
   PubMed Web of Science ®Google Scholar
• Fu , P. P. , Chou , M. W. , Xia , Q. , Yang , Y. C. , Yan , J. , Doerge , D. R. and Chan , P. C. 2001 . Genotoxic pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides—Mechanisms leading to DNA adduct formation and tumorigenicity . J. Environ. Sci. Health C Environ. Carcinogen. Ecotoxicol. Rev. , 19 : 353 – 386 .
   Web of Science ®Google Scholar
• Fu , P. P. , Xia , Q. , Lin , G. and Chou , M. W. 2004 . Pyrrolizidine alkaloids—Genotoxicity, metabolism enzymes, metabolic activation, and mechanisms . Drug Metab. Rev. , 36 : 1 – 55 .
   PubMed Web of Science ®Google Scholar
• Fu , P. P. , Xia , Q. , Chou , M. W. and Lin , G. 2007 . Detection, hepatotoxicity, and tumorigenicity of pyrrolizidine alkaloids in Chinese herbal plants and herbal dietary supplements . J. Food Drug Anal. , 15 : 400 – 415 .
   Web of Science ®Google Scholar
• Fuhr , U. 2000 . Induction of drug metabolising enzymes: Pharmacokinetic and toxicological consequences in humans . Clin. Pharmacokinet. , 38 : 493 – 504 .
   PubMed Web of Science ®Google Scholar
• Furmanowa , M. , Guzewska , J. and Beldowska , B. 1983 . Mutagenic effects of aqueous extracts of Symphytum officinale L. and of its alkaloidal fractions . J. Appl. Toxicol. , 3 : 127 – 130 .
   PubMed Web of Science ®Google Scholar
• Furuya , T. and Araki , K. 1968 . Studies on constituents of crude drugs. I. Alkaloids of Symphytum officinale Linn . Chem. Pharm. Bull (Tokyo) , 16 : 2512 – 2516 .
   PubMed Web of Science ®Google Scholar
• Garrett , B. J. , Cheeke , P. R. , Miranda , C. L. , Goeger , D. E. and Buhler , D. R. 1982 . Consumption of poisonous plants (Senecio jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: Chronic toxicity, mineral metabolism, and hepatic drug-metabolizing enzymes . Toxicol. Lett. , 10 : 183 – 188 .
   PubMed Web of Science ®Google Scholar
• Gomes , M. F. , de Oliveira Massoco , C. , Xavier , J. G. and Bonamin , L. V. 2007 . Comfrey (Symphytum Officinale. L.) and experimental hepatic carcinogenesis: A short-term carcinogenesis model study . Evidence Based Complement. Altern. Med. , doi: 10.1093/ecam/nem172
   PubMedGoogle Scholar
• Gray , D. E. , Porter , A. , O'Neill , T. , Harris , R. K. and Rottinghaus , G. E. 2004 . A rapid cleanup method for the isolation and concentration of pyrrolizidine alkaloids in comfrey root . J. Am.Off. Assoc. Chem. Int. , 87 : 1049 – 1057 .
   Google Scholar
• Guo , L. , Lobenhofer , E. K. , Wang , C. , Shippy , R. , Harris , S. C. , Zhang , L. , Mei , N. , Chen , T. , Herman , D. , Goodsaid , F. M. , Hurban , P. , Phillips , K. L. , Xu , J. , Deng , X. , Sun , Y. A. , Tong , W. , Dragan , Y. P. and Shi , L. 2006 . Rat toxicogenomic study reveals analytical consistency across microarray platforms . Nat. Biotechnol. , 24 : 1162 – 1169 .
   PubMed Web of Science ®Google Scholar
• Guo , L. , Mei , N. , Dial , S. , Fuscoe , J. and Chen , T. 2007 . Comparison of gene expression profiles altered by comfrey and riddelliine in rat liver . BMC Bioinformatics , 8 ( suppl. 7 ) : S22
   PubMed Web of Science ®Google Scholar
• Gyorik , S. and Stricker , H. 2009 . Severe pulmonary hypertension possibly due to pyrrolizidine alkaloids in polyphytotherapy . Swiss. Med. Weekly , 139 : 210 – 211 .
   PubMed Web of Science ®Google Scholar
• Haworth , S. , Lawlor , T. , Mortelmans , K. , Speck , W. and Zeiger , E. 1983 . Salmonella mutagenicity test results for 250 chemicals . Environ. Mutagen. , 5 ( suppl. 1 ) : 1 – 142 .
   PubMedGoogle Scholar
• Hirono , I. , Haga , M. , Fujii , M. , Matsuura , S. , Matsubara , N. , Nakayama , M. , Furuya , T. , Hikichi , M. , Takanashi , H. , Uchida , E. , Hosaka , S. and Ueno , I. 1979 . Induction of hepatic tumors in rats by senkirkine and symphytine . JNCI , 63 : 469 – 472 .
   PubMed Web of Science ®Google Scholar
• Hirono , I. , Mori , H. and Haga , M. 1978 . Carcinogenic activity of Symphytum officinale . JNCI , 61 : 865 – 869 .
   PubMed Web of Science ®Google Scholar
• Huxtable , R. J. , Luthy , J. and Zweifel , U. 1986 . Toxicity of comfrey–pepsin preparations . N. Engl. J. Med. , 315 : 1095
   PubMed Web of Science ®Google Scholar
• Integrated Laboratory Systems. 1997. Comfrey and one of its constituent alkaloids symphytine http://ntpniehsnihgov/ntp/htdocs/Chem_Background/ExSumPdf/Comfreypdf (http://ntpniehsnihgov/ntp/htdocs/Chem_Background/ExSumPdf/Comfreypdf)
   Google Scholar
• International Programme on Chemical Safety . 1989 . Pyrrolizidine alkaloids health and safety guide , Health and Safety Criteria Guide 26 Geneva, , Switzerland : WHO .
   Google Scholar
• Kim , N. C. , Oberlies , N. H. , Brine , D. R. , Handy , R. W. , Wani , M. C. and Wall , M. E. 2001 . Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography . J. Nat. Prod. , 64 : 251 – 253 .
   PubMed Web of Science ®Google Scholar
• Koll , R. , Buhr , M. , Dieter , R. , Pabst , H. , Predel , H. G. , Petrowicz , O. , Giannetti , B. , Klingenburg , S. and Staiger , C. 2004 . Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: Results of a multicenter, randomized, placebo-controlled, double-blind study . Phytomedicine , 11 : 470 – 477 .
   PubMed Web of Science ®Google Scholar
• Lame , M. W. , Morin , D. , Jones , A.D. , Segall , H. J. and Wilson , D. W. 1990 . Isolation and identification of a pyrrolic glutathione conjugate metabolite of the pyrrolizidine alkaloid monocrotaline . Toxicol. Lett. , 51 : 321 – 329 .
   PubMed Web of Science ®Google Scholar
• Lame , M. W. , Jones , A. D. , Morin , D. and Segall , H. J. 1991 . Metabolism of [14C]monocrotaline by isolated perfused rat liver . Drug Metab. Dispos. , 19 : 516 – 524 .
   PubMed Web of Science ®Google Scholar
• Lin , G. , Cui , Y. Y. and Hawes , E. M. 2000 . Characterization of rat liver microsomal metabolites of clivorine, an hepatotoxic otonecine-type pyrrolizidine alkaloid . Drug Metab. Dispos. , 28 : 1475 – 1483 .
   PubMed Web of Science ®Google Scholar
• Lin , G. , Cui , Y. Y. , Liu , X. Q. and Wang , Z. T. 2002 . Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloid clivorine . Chem. Res. Toxicol. , 15 : 1421 – 1428 .
   PubMed Web of Science ®Google Scholar
• Lin , G. , Nnane , I. P. and Cheng , T. Y. 1999 . The effects of pretreatment with glycyrrhizin and glycyrrhetinic acid on the retrorsine-induced hepatotoxicity in rats . Toxicon , 37 : 1259 – 1270 .
   PubMed Web of Science ®Google Scholar
• Lin , G. , Zhou , K. Y. , Zhao , X. G. , Wang , Z. T. and But , P. P. 1998 . Determination of hepatotoxic pyrrolizidine alkaloids by on-line high performance liquid chromatography mass spectrometry with an electrospray interface . Rapid Commun. Mass. Spectrom. , 12 : 1445 – 1456 .
   PubMed Web of Science ®Google Scholar
• Liu , F. , Wan , S. Y. , Jiang , Z. , Li , S. F. , Ong , E. S. and Osorio , J. C. 2009 . Determination of pyrrolizidine alkaloids in comfrey by liquid chromatography–electrospray ionization mass spectrometry . Talanta , 80 : 916 – 923 .
   PubMed Web of Science ®Google Scholar
• Martignoni , M. , Groothuis , G. M. and de Kanter , R. 2006 . Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction . Expert. Opin. Drug Metab. Toxicol. , 2 : 875 – 894 .
   PubMed Web of Science ®Google Scholar
• Mattocks , A. R. 1967 . Detection of pyrroli-zidine alkaloids on thin-layer chromato-grams . J. Chromatogr. , 27 : 505 – 508 .
   PubMed Web of Science ®Google Scholar
• Mattocks , A. R. 1986 . Chemistry and toxicology of pyrrolizidine alkaloids , New York : Academic Press .
   Google Scholar
• Mei , N. , Guo , L. , Fu , P. P. , Heflich , R. H. and Chen , T. 2005 . Mutagenicity of comfrey (Symphytum officinale) in rat liver . Br. J. Cancer , 92 : 873 – 875 .
   PubMed Web of Science ®Google Scholar
• Mei , N. , Guo , L. , Zhang , L. , Shi , L. , Sun , Y.A. , Fung , C. , Moland , C. L. , Dial , S. L. , Fuscoe , J. C. and Chen , T. 2006 . Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale) . BMC Bioinformatics , 7 ( suppl. 2 ) : S16
   PubMed Web of Science ®Google Scholar
• Mei , N. , Heflich , R. H. , Chou , M. W. and Chen , T. 2004 . Mutations induced by the carcinogenic pyrrolizidine alkaloid riddelliine in the liver cII gene of transgenic Big Blue rats . Chem. Res. Toxicol. , 17 : 814 – 818 .
   PubMed Web of Science ®Google Scholar
• Mei , X. and Chen , T. 2007 . The mutant frequency and types of mutations induced by comfrey in the lungs of transgenic Big Blue rats . J. Food Drug Anal. , 15 : 458 – 465 .
   Web of Science ®Google Scholar
• National Toxicology Program. 1978. Bioassay of lasiocarpine for possible carcinogenicity (CAS No. 303-34-4) http://ntpniehsnihgov/?objectid=07032341-E34A-AFA1-C61487B8222FC5A8 (http://ntpniehsnihgov/?objectid=07032341-E34A-AFA1-C61487B8222FC5A8)
   Google Scholar
• National Toxicology Program. 2008. Report on carcinogen. Fed. Reg. 73:23463–23465 http://ntp.niehs.nih.gov/files/23473_FR_23484_23430Apr22008_23508.pdf (http://ntp.niehs.nih.gov/files/23473_FR_23484_23430Apr22008_23508.pdf)
   Google Scholar
• Oberlies , N. H. , Kim , N. C. , Brine , D. R. , Collins , B. J. , Handy , R. W. , Sparacino , C. M. , Wani , M. C. and Wall , M. E. 2004 . Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids . Public Health Nutr. , 7 : 919 – 924 .
   PubMed Web of Science ®Google Scholar
• Prakash , A. S. , Pereira , T. N. , Reilly , P. E. and Seawright , A. A. 1999 . Pyrrolizidine alkaloids in human diet . Mutat. Res. , 443 : 53 – 67 .
   PubMed Web of Science ®Google Scholar
• Rao , M. S. and Reddy , J. K. 1978 . Malignant neoplasms in rats fed lasiocarpine . Br. J. Cancer , 37 : 289 – 293 .
   PubMed Web of Science ®Google Scholar
• Reid , M. J. , Lame , M. W. , Morin , D. , Wilson , D. W. and Segall , H. J. 1998 . Involvement of cytochrome P450 3A in the metabolism and covalent binding of 14C-monocrotaline in rat liver microsomes . J. Biochem. Mol. Toxicol. , 12 : 157 – 166 .
   PubMed Web of Science ®Google Scholar
• Ridker , P. M. and McDermott , W. V. 1989 . Comfrey herb tea and hepatic veno-occlusive disease . Lancet , 8639 : 657 – 658 .
   Google Scholar
• Ridker , P. M. , Ohkuma , S. , McDermott , W. V. , Trey , C. and Huxtable , R. J. 1985 . Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements . Gastroenterology , 88 : 1050 – 1054 .
   PubMed Web of Science ®Google Scholar
• Ridker , P. N. and McDermont , W. V. 1989 . Hepatotoxicity due to comfrey herb tea . Am. J. Med. , 87 : 701
   PubMed Web of Science ®Google Scholar
• Rode , D. 2002 . Comfrey toxicity revisited . Trends Pharmacol. Sci. , 23 : 497 – 499 .
   PubMed Web of Science ®Google Scholar
• Roeder , E. 1995 . Medicinal plants in Europe containing pyrrolizidine alkaloids . Pharmazie , 50 : 83 – 98 .
   PubMed Web of Science ®Google Scholar
• Roitman , J. N. 1981 . Comfrey and liver damage . Lancet , 8226 : 944
   Google Scholar
• Sakakura , C. E. , Neto , R. S. , Bellucci , M. , Wenzel , A. , Scaf , G. and Marcantonio , E. Jr. 2008 . Influence of homeopathic treatment with comfrey on bone density around titanium implants: a digital subtraction radiography study in rats . Clin. Oral Implants Res. , 19 : 624 – 628 .
   PubMed Web of Science ®Google Scholar
• Schaneberg , B. T. , Molyneux , R. J. and Khan , I. A. 2004 . Evaporative light scattering detection of pyrrolizidine alkaloids . Phytochem. Anal. , 15 : 36 – 39 .
   PubMed Web of Science ®Google Scholar
• Schoental , R. , Fowler , M. E. and Coady , A. 1970 . Islet cell tumors of the pancreas found in rats given pyrrolizidine alkaloids from Amsinckia intermedia Fisch and Mey and from Heliotropium supinum L . Cancer Res. , 30 : 2127 – 2131 .
   PubMed Web of Science ®Google Scholar
• Snider , S. 1991 . Herbal teas and toxicity . FDA Consumer , 25 : 30 – 33 .
   Google Scholar
• Stickel , F. and Seitz , H. K. 2000 . The efficacy and safety of comfrey . Public Health Nutr. , 3 : 501 – 508 .
   PubMed Web of Science ®Google Scholar
• Svoboda , D. J. and Reddy , J. K. 1972 . Malignant tumors in rats given lasiocarpine . Cancer Res. , 32 : 908 – 913 .
   PubMed Web of Science ®Google Scholar
• Takanashi , H. , Umeda , M. and Hirono , I. 1980 . Chromosomal aberrations and mutation in cultured mammalian cells induced by pyrrolizidine alkaloids . Mutat. Res. , 78 : 67 – 77 .
   PubMed Web of Science ®Google Scholar
• Vollmer , J. J. , Steiner , N. C. , Larsen , G. Y. , Muirhead , K. M. and Molyneux , R. J. 1987 . Pyrrolizidine alkaloids: testing for toxic constituents of comfrey . J. Chem. Educ. , 64 : 1027 – 1030 .
   Web of Science ®Google Scholar
• Weston , C. F. , Cooper , B. T. , Davies , J. D. and Levine , D. F. 1987 . Veno-occlusive disease of the liver secondary to ingestion of comfrey . Br. Med. J. (Clin. Res. Ed.) , 295 : 183
   PubMedGoogle Scholar
• White , R. D. , Krumperman , P. H. , Cheeke , P. R. and Buhler , D. R. 1983 . An evaluation of acetone extracts from six plants in the Ames mutagenicity test . Toxicol. Lett. , 15 : 25 – 31 .
   PubMed Web of Science ®Google Scholar
• Willett , K. L. , Roth , R. A. and Walker , L. 2004 . Workshop overview: Hepatotoxicity assessment for botanical dietary supplements . Toxicol. Sci. , 79 : 4 – 9 .
   PubMed Web of Science ®Google Scholar
• Williams , D. E. , Reed , R. L. , Kedzierski , B. , Ziegler , D. M. and Buhler , D. R. 1989 . The role of flavin-containing monooxygenase in the N-oxidation of the pyrrolizidine alkaloid senecionine . Drug Metab. Dispos. , 17 : 380 – 386 .
   PubMed Web of Science ®Google Scholar
• Winship , K. A. 1991 . Toxicity of comfrey . Adverse Drug React. Toxicol. Rev. , 10 : 47 – 59 .
   PubMedGoogle Scholar
• Wuilloud , J. C. , Gratze , S. R. , Gamble , B. M. and Wolnik , K. A. 2004 . Simultaneous analysis of hepatotoxic pyrrolizidine alkaloids and N-oxides in comfrey root by LC-ion trap mass spectrometry . Analyst , 129 : 150 – 156 .
   PubMed Web of Science ®Google Scholar
• Xia , Q. , Chou , M. W. , Edgar , J. A. , Doerge , D. R. and Fu , P. P. 2006 . Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine . Cancer Lett. , 231 : 138 – 145 .
   PubMed Web of Science ®Google Scholar
• Yamanaka , H. , Nagao , M. , Sugimura , T. , Furuya , T. , Shirai , A. and Matsushima , T. 1979 . Mutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test . Mutat. Res. , 68 : 211 – 216 .
   PubMed Web of Science ®Google Scholar
• Yan , C. C. and Huxtable , R. J. 1996 . Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat . Biochem. Pharmacol. , 51 : 375 – 379 .
   PubMed Web of Science ®Google Scholar
• Yang , Y. C. , Yan , J. , Doerge , D. R. , Chan , P. C. , Fu , P. P. and Chou , M. W. 2001 . Metabolic activation of the tumorigenic pyrrolizidine alkaloid, riddelliine, leading to DNA adduct formation in vivo . Chem. Res. Toxicol. , 14 : 101 – 109 .
   PubMed Web of Science ®Google Scholar
• Yeong , M. L. , Clark , S. P. , Waring , J. M. , Wilson , R. D. and Wakefield , S. J. 1991 . The effects of comfrey derived pyrrolizidine alkaloids on rat liver . Pathology , 23 : 35 – 38 .
   PubMed Web of Science ®Google Scholar
• Yeong , M. L. , Swinburn , B. , Kennedy , M. and Nicholson , G. 1990 . Hepatic veno-occlusive disease associated with comfrey ingestion . J. Gastroenterol. Hepatol. , 5 : 211 – 214 .
   PubMed Web of Science ®Google Scholar
• Yoon , J. S. , Mason , J. M. , Valencia , R. , Woodruff , R. C. and Zimmering , S. 1985 . Chemical mutagenesis testing in Drosophila. IV. Results of 45 coded compounds tested for the National Toxicology Program . Environ. Mutagen , 7 : 349 – 367 .
   PubMedGoogle Scholar
• Zhou , S. , Koh , H. L. , Gao , Y. , Gong , Z. Y. and Lee , E. J. 2004 . Herbal bioactivation: The good, the bad and the ugly . Life Sci. , 74 : 935 – 968 .
   PubMed Web of Science ®Google Scholar