Comfrey (Symphytum Officinale. l.) and Experimental Hepatic Carcinogenesis: A Short-term Carcinogenesis Model Study

Comfrey or Symphytum officinale (L.) (Boraginaceae) is a very popular plant used for therapeutic purposes. Since the 1980s, its effects have been studied in long-term carcinogenesis studies, in which Comfrey extract is administered at high doses during several months and the neoplastic hepatic lesions are evaluated. However, the literature on this topic is very poor considering the studies performed under short-term carcinogenesis protocols, such as the ‘resistant hepatocyte model’ (RHM). In these studies, it is possible to observe easily the phenomena related to the early phases of tumor development, since pre-neoplastic lesions (PNLs) rise in about 1–2 months of chemical induction. Herein, the effects of chronic oral treatment of rats with 10% Comfrey ethanolic extract were evaluated in a RHM. Wistar rats were sequentially treated with N-nitrosodiethylamine (ip) and 2-acetilaminofluorene (po), and submitted to hepatectomy to induce carcinogenesis promotion. Macroscopic/microscopic quantitative analysis of PNL was performed. Non-parametric statistical tests (Mann–Whitney and χ2) were used, and the level of significance was set at P ≤ 0.05. Comfrey treatment reduced the number of pre-neoplastic macroscopic lesions up to 1 mm (P ≤ 0.05), the percentage of oval cells (P = 0.0001) and mitotic figures (P = 0.007), as well as the number of Proliferating Cell Nuclear Antigen (PCNA) positive cells (P = 0.0001) and acidophilic pre-neoplastic nodules (P = 0.05). On the other hand, the percentage of cells presenting megalocytosis (P = 0.0001) and vacuolar degeneration (P = 0.0001) was increased. Scores of fibrosis, glycogen stores and the number of nucleolus organizing regions were not altered. The study indicated that oral treatment of rats with 10% Comfrey alcoholic extract reduced cell proliferation in this model.

[1]  B. Patwardhan,et al.  DNA Microarrays in Herbal Drug Research , 2006, Evidence-based complementary and alternative medicine : eCAM.

[2]  Tao Chen,et al.  Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale) , 2006, BMC Bioinformatics.

[3]  P. Fu,et al.  Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids , 2006, Toxicology and industrial health.

[4]  K. Wolnik,et al.  Investigation of pyrrolizidine alkaloids and their N-oxides in commercial comfrey-containing products and botanical materials by liquid chromatography electrospray ionization mass spectrometry. , 2005, Journal of AOAC International.

[5]  N. Mei,et al.  Mutagenicity of comfrey (Symphytum Officinale) in rat liver , 2005, British Journal of Cancer.

[6]  Dorena Rode,et al.  Comfrey toxicity revisited. , 2002, Trends in pharmacological sciences.

[7]  John F. Young,et al.  Toxicokinetics of riddelliine, a carcinogenic pyrrolizidine alkaloid, and metabolites in rats and mice. , 2002, Toxicology and applied pharmacology.

[8]  E. Laconi,et al.  A growth-constrained environment drives tumor progression in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R W Handy,et al.  Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography. , 2001, Journal of natural products.

[10]  F. Stickel,et al.  The efficacy and safety of comfrey , 2000, Public Health Nutrition.

[11]  E. Laconi,et al.  Liver regeneration in response to partial hepatectomy in rats treated with retrorsine: a kinetic study. , 1999, Journal of hepatology.

[12]  F. Chung The prevention of lung cancer induced by a tobacco-specific carcinogen in rodents by green and black Tea. , 1999, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[13]  M. Klepser,et al.  Unsafe and potentially safe herbal therapies. , 1999, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[14]  M. Clemens,et al.  Effect of dietary phytochemicals on cancer development (review) , 1998, International journal of molecular medicine.

[15]  R. Coulombe,et al.  Pyrrolizidine alkaloid-induced DNA-protein cross-links. , 1995, Carcinogenesis.

[16]  A. Olìnescu,et al.  Action of some proteic and carbohydrate components of Symphytum officinale upon normal and neoplastic cells. , 1993, Roumanian archives of microbiology and immunology.

[17]  B. Swinburn,et al.  Hepatic veno‐occlusive disease associated with comfrey ingestion , 1990, Journal of gastroenterology and hepatology.

[18]  W. Göggelmann,et al.  [Studies on the effect of an alkaloid extract of Symphytum officinale on human lymphocyte cultures]. , 1989, Planta medica.

[19]  E. Röder,et al.  Wirkung eines Alkaloidextraktes von Symphytum officinale auf menschliche Lymphocytenkulturen , 1989 .

[20]  J. Lewis,et al.  Drug-induced liver disease. , 1989, The Medical clinics of North America.

[21]  S. Palmer,et al.  The role of non-nutritive dietary constituents in carcinogenesis. , 1986, The Surgical clinics of North America.

[22]  E. Farber,et al.  Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine. , 1985, Cancer research.

[23]  P. Ridker,et al.  Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. , 1985, Gastroenterology.

[24]  A. Mattocks TOXIC PYRROLIZIDINE ALKALOIDS IN COMFREY , 1980, The Lancet.

[25]  I Hirono,et al.  Induction of hepatic tumors in rats by senkirkine and symphytine. , 1979, Journal of the National Cancer Institute.

[26]  I Hirono,et al.  Carcinogenic activity of Symphytum officinale. , 1978, Journal of the National Cancer Institute.

[27]  D. Solt,et al.  New principle for the analysis of chemical carcinogenesis , 1976, Nature.

[28]  H. Zander INFECTIOUS-DISEASE HYPOTHESIS OF HUMAN LEUKÆMIA AND LYMPHOMA , 1975, The Lancet.

[29]  W. Bailey Pathology of Domestic Animals , 1964 .

[30]  M. Dagli,et al.  Beta‐carotene reduces the ductular (oval) cell reaction in the liver of Wistar rats submitted to the resistant hepatocyte model of carcinogenesis , 1998, Pathology.

[31]  E. Laconi,et al.  Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine. , 1995, Carcinogenesis.

[32]  J. Maciejowski,et al.  Identification and assessment of nucleolar organizer regions (NORs)--technical problems. , 1994, Polish journal of pathology : official journal of the Polish Society of Pathologists.

[33]  M. Yeong,et al.  Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats. , 1993, International journal of experimental pathology.

[34]  M. Yeong,et al.  The Effects of Comfrey Derived Pyrrolidine Alkaloids on Rat Liver , 1991, Pathology.

[35]  T. Shimoyama,et al.  Suppressive effect of wasabi (pungent Japanese spice) on gastric carcinogenesis induced by MNNG in rats. , 1991, Nutrition and cancer.

[36]  D. Sarma,et al.  Hepatocarcinogenesis: a dynamic cellular perspective. , 1987, Laboratory investigation; a journal of technical methods and pathology.

[37]  Fernando de Oliveira,et al.  Confrei: virtudes e problemas , 1986 .

[38]  M. Black,et al.  Drug induced liver disease. , 1983, Postgraduate medical journal.

[39]  E. Farber,et al.  The sequential analysis of cancer development. , 1980, Advances in cancer research.

[40]  P. Kennedy Pathology of domestic animals , 1970 .