Pharmacological/Toxicologic Effects

18.4 Pharmacological/Toxicologic Effects

An excellent resource for toxicology information pertaining to comfrey is Mattocks (1986).

18.4.1 Gastrointestinal Effects

In an in vitro study using rat gastric tissue, researchers showed that an extract of 10 mg of dried comfrey leaves (S. officinale) homogenized in 1 mL of Kreb's solution increased the release of

prostaglandin F 2 α and 6-keto-prostaglandin F 1 α (Stamford and Tavares, 1983). As numerous prostaglandins have been found to protect the gastric mucosa, there may be a biologic basis for use of

comfrey as a treatment for peptic ulcers.

18.4.2 Hepatotoxicity

Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey) (USP, 1998). However, some products are derived from Symphytum x uplandicum Nyman (Russian comfrey) or Symphytum asperum Lepech (prickly comfrey), which appear to be more toxic than common comfrey (Anonymous, 1998). Russian comfrey and prickly comfrey contain a very toxic pyrrolizidine alkaloid (PA) called echimidine that common comfrey does not contain (Tyler, 1994). Although common comfrey does not contain echimidine, it does contain other hepatotoxic PAs. These alkaloids include 7-acetylintermedine, 7-acetyllycopsamine, their unacetylated precursors, and symphytine (Tyler, 1993).

These PAs can cause hepatic venoocclusive disease with zonal or focal hemorrhagic hepatic necrosis, damage to the endothelium of the central and sublobular veins, hepatocyte swelling, biliary hyperplasia, and marked fibrosis (Abbott, 1988). These alkaloids can also cause pulmonary fibrosis (Svoboda and Reddy, 1972).

Several studies in rats have shown liver damage caused by comfrey. In one study (Yeong et al., 1991), three groups of mice received different doses of PAs derived from the fresh roots and leaves of Symphytum x uplandicum Nyman (Russian comfrey). A single dose of 200 mg/kg was given to group I rats, a dose of 100 mg/kg three times a week was given to group II rats, and dose of 50 mg/kg three times a week for 3 wk was given to group III rats. All of the rats developed dose-dependent liver damage evident by light and electron microscopy. Group I rats showed swelling of hepatocytes and hemorrhagic necrosis of perivenular cells with preservation of sinusoidal walls and endothelial cells. Group I rats also developed noticeable extravasation of red blood cells. Group II and III rats had similar changes but with more severe necrosis. Loss of sinusoidal lining cells and disruption of hepatocyte cellular margins was found in both group II and group III rats. All of these histologic changes are indicative of hepatic venoocclusive disease caused by PAs.

Another study examined the activity of various hepatic drug-metabolizing enzymes in liver homogenates of three groups of six male Long-Evans rats fed Another study examined the activity of various hepatic drug-metabolizing enzymes in liver homogenates of three groups of six male Long-Evans rats fed

Another study involved injecting eight adult rats (four male, four female) with 50 mg/kg of comfrey (Symphytum × uplandicum Nymann leaves, roots, and stems) derived alkaloids per week for 6 wk (Yeong et al., 1993). One week after the last dose was given, the rats were killed and their livers were examined with light and electron microscopy. Light microscopy showed excessive sinusoidal congestion, loss of definition of hepatocyte cellular membranes, and mild zone 3 necrosis. Ultrastructural damage such as endothelial sloughing and loss of hepatocyte microvilli was evident. The most significant finding in this study was florid bleb formation. Formation of blebs is an indicator of impending irreversible liver damage. Blebs were observed in the sinsoidal borders of hepatocytes. Some of these blebs occluded the sinusoidal lumina. The space of Disse was damaged by deposition of collagen and was extensively dilated. These findings were not found in the two control groups. All eight experimental rats showed the same liver damage described previously.

Some have also questioned the safety of comfrey externally. According to one toxicologic researcher (Mattocks, 1980), external use of comfrey should not be hazardous because the PAs must be converted to the toxic free PAs by the liver (Mattocks, 1968).

An animal study supports Mattock's hypothesis. The absorption of comfrey through unbroken skin is very low and should not cause toxicity. A Swiss experiment with rats showed that 0.1–0.4% of a dermal dose of 194 mg of alkaloid N-oxides/kg (extracted from the roots of Polish S. officinale) was recovered in the urine 48 h later (Brauchli et al., 1982). The researchers noted that the orally ingested alkaloids showed up in the urine at 20–50 times the concentration of the alkaloids found in the urine after dermal administration. Of the dermally absorbed alkaloids, only a small amount was converted to the toxic free alkaloids. These researchers concluded that short-term dermal use of comfrey should not be dangerous.

18.4.3 Carcinogenicity/Mutagenicity

Long-term studies in animals have shown that comfrey is carcinogenic (USP, 1998). This carcinogenicity has been associated with the PAs found in comfrey. Several studies involving rats have made this correlation.

In 1978, the results of a study involving Symphytum officinale were published in the Journal of the National Cancer Institute (Hirono et al., 1978b).

Over a 480- to 600-d period, seven groups of inbred strain ACI rats were fed dried comfrey leaves (S. officinale) or dried comfrey roots (S. officinale). Three groups of rats consisting of 19–22 rats were fed comfrey leaves as 0.5–33% of their diet, and four groups consisting of 15–24 rats were fed comfrey roots as 1–4% of their diets. A control group was fed a normal diet. All groups of rats fed comfrey roots or leaves developed hepatocellular adenomas, while the rats in the control groups did not develop liver

tumors. The results also showed that the highest incidence of liver tumors occurred in those rats being fed comfrey roots.

A study published almost 1 yr later showed very similar results. Twenty rats were injected with 13 mg/kg of symphytine (a PA common in comfrey) (10% of the LD 50 ) extracted from dried comfrey roots,

while a control group received intraperitoneal injections of 0.9% sodium chloride (Hirono et al., 1978a). Of the rats injected with symphytine, four developed liver tumors; three developed hemangioendothelial sarcomas, and one developed liver cell adenoma. The rats in the control group developed no liver tumors. This pattern of carcinogenicity was similar to that seen in the previous study using comfrey leaves.

Lasiocarpine is another carcinogenic PA. Lasiocarpine has been detected in S. officinale roots by thin- layer chrommatography (TLC) at a concentration of 0.0058% (Winship, 1991). An experiment conducted by Northwestern University Medical School involved feeding 20 male inbred strain F-344 rats lasiocarpine at a concentration of 50 ppm over 55 wk (Rao and Reddy, 1978). Ten control rats were fed a diet without lasiocarpine. At the end of 59 wk, necropsies were performed on all animals (survivors were killed along with the control animals). None of the control rats had any abnormalities based on light and electron microscopy. Of the 20 experimental rats, 17 developed malignancies. Forty-

five percent (nine) developed angiosarcomas while 35% (seven) developed hepatocellular carcinomas. One rat developed malignant adnexal tumor of the skin and one developed lymphoma. Four rats with angiosarcoma developed lung mestases while one rat with hepatocellular carcinoma developed lung metastases.

Mutagenicity has been demonstrated by many PAs using several standard tests (Mattocks, 1986).

18.4.4 LD 50

It has been stated that humans appear more sensitive to the toxic affects of the alkaloids than are rats, meaning that human deaths have occurred at much lower LD 50 s when compared to rats (Huxtable,

1989). However, it is important to note that the LD 50 varies among the alkaloids, and because the plant contains 1989). However, it is important to note that the LD 50 varies among the alkaloids, and because the plant contains

example, the LD 50 of one alkaloid, retrosine, is 34 mg/kg in male rats, but 800 mg/kg in guinea pigs.