Metabolism, genotoxicity, and carcinogenicity of comfrey

Abstract

Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction.

FIGURE 1

The pictures of comfrey (Symphytum officinale): (A) whole plant; (B) comfrey roots.

FIGURE 2

Structures of representative pyrrolizidine alkaloids found in comfrey.

FIGURE 3

Metabolism of lasiocarpine. Lasiocarpine, a pyrrolizidine alkaloid found in comfrey, undergoes metabolic activation to its metabolites including 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) that reacts with DNA, leading to DNA adduct formation and liver tumor induction.

FIGURE 4

Tumor incidence in the livers of rats treated with comfrey. Male and female ACI rats were fed a diet containing comfrey leaves (A) or comfrey roots (B) at different percentages for up to 600 d. All liver tissues were autopsied at the termination of experiment. No liver tumors were observed in the control group. Data from Hirono et al. (1978).

FIGURE 5

³²P-Postlabeling/HPLC analysis of DHP-derived DNA adducts formed in the liver. Female F344 rats were treated with 1 mg/kg of riddelliine (A), 120 μl per day comfrey root extract (B), and 200 μl per day comfrey compound oil (C) by gavage for 3 consecutive days, and sacrificed 24 h after last treatment for DNA adduct analysis. Data from Chou and Fu (2006).

FIGURE 6

The cII mutant frequencies in the livers of rats treated with comfrey roots. Male Big Blue transgenic rats were fed a diet containing comfrey roots at different percentages (2, 4, and 8%) for 3 mo. Data represent means ± SD from six rats in each group. The comfrey-induced mutant frequencies were significantly higher than for controls (p < .05).