The MF for rats fed comfrey was 146☑5 × 10 −6, which was significantly greater than the MF for control rats, 30☑6 × 10 −6 ( P<0.001, ANOVA, Holm–Sidak test).
Mutant frequencies (MFs) were determined for the liver cII gene of the rats treated with comfrey ( Table 1). The animals were killed after 12 weeks of treatment. Groups of six 6-week-old male Big Blue rats (Taconic Laboratories, Germantown, NY, USA) were fed either a basal diet or the comfrey diet. The comfrey roots were ground and then blended with basal diet powder (NIH-31 pellets, Purina Mills International, Brentwood, MO, USA) in a Hobart Mixer to make a 2% comfrey root diet. Based on a minimum effect on weight gain, lack of overt toxicity to the liver, and a maximum effect on mutagenicity, a diet containing 2% comfrey root was chosen for the mutagenesis experiment (see Supplements 1 and 2).
To determine an appropriate dose for treatment, a preliminary experiment was conducted by feeding diets containing 2, 4, and 8% comfrey. The PAs detected were similar to those reported previously ( Betz et al, 1994), and included symphytine, 7-acetyllycopsamine, and 7-acetylintermedine as major components in near equal amounts intermedine and lycopsamine were present in relatively smaller quantity (data not shown).
Pyrrolizidine alkaloids in the comfrey roots were determined by mass spectral analysis. Comfrey roots were obtained from Camas Prairie Products (Trout Lake, WA, USA). The treatment schedule was based on a previous study that evaluated the carcinogenicity of comfrey ( Hirono et al, 1978). In this study, we evaluated the mutagenicity of comfrey in the liver cII gene of Big Blue rats. This inspired us to investigate the mutagenicity of comfrey in rat liver, a target tissue for its carcinogenesis, by using a transgenic rat mutational model ( Dycaico et al, 1994). Although induction of hepatic tumours has been associated with the pyrrolizidine alkaloids (PAs) that are present in comfrey, and PAs are genotoxic and carcinogenic by binding to liver DNA in humans and animals ( Prakash et al, 1999 Fu et al, 2004), a comprehensive study of comfrey mutagenesis has not been conducted. There is little known about the mechanism of tumour induction by comfrey. There are presently, however, no restrictions on the use of comfrey in many parts of the world. This concern led the US Food and Drug Administration to request voluntary removal of products containing comfrey from the market in 2001 ( FDA, 2001). Although there are no epidemiological data regarding the carcinogenicity of comfrey, these adverse effects have raised questions of its potential carcinogenicity in humans. It induced hepatic veno-occlusive disease in humans ( Ridker et al, 1985 Weston et al, 1987 Bach et al, 1989 Ridker and McDermott, 1989 Yeong et al, 1990) and hepatocellular adenomas and haemangioendothelial sarcomas in rat liver ( Hirono et al, 1978). Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. It has been used as an herbal medicine for more than 2000 years to treat broken bones, tendon damage, ulcerations in the gastrointestinal tract, lung congestion, and joint inflammation, and to promote wound healing ( Rode, 2002). Comfrey is consumed by humans as a vegetable and a tea. Comfrey ( Symphytum officinale) is a tall perennial plant with large hairy leaves and small purple flowers ( Winship, 1991 Betz et al, 1994).
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