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IS CANAVANINE HARMFUL TO HUMANS?

GERALD A. ROSENTHAL

Being a protective allelochemical, L-canavanine must have some intrinsic toxicity or it would not be able to serve in higher plant chemical defense against insects, other animals, and microorganisms. As amply documented elsewhere on this web site, the tobacco hornworm, Manduca sexta [Sphingidae] is highly suspectible to the pernicous effects of this higher plant nonprotein amino acid. It is for this (and other reasons) that it was selected as the model system for studies of the antimetabolic effects of canavanine in insects.

At the other end of the response spectrum, are insects such as the bruchid beetle, Caryedes brasiliensis and the weevil, Sternechtus tuberculatus which oviposit their eggs on legumes whose seeds are very rich in canavanine. The newly emerged larvae feed exclusively on the canavanine-laden cotyledons (the food storage organ) of the seed. [To learn more about these canavanine-adapted insects return to the home page and move to the appropriate link].

The first suggestion that canavanine may be deleterious to humans came from studies of the primate, Macaca fascicularis (cynomolgus macaque) that was fed alfalfa sprouts (Malinow et al., 1982). Canavanine constitutes about 2% of the weight of the fresh sprout.
When these animals were maintained on a diet that was supplemented with 40% alfalfa sprouts for 7 months they developed a systemic lupus erythematosus-like syndrome.
SLE is a serious disease of humans. It is significant that macaques that developed the disease ceased to exhibit adverse symptoms when alfalfa was removed from their diet.
When the animals were fed a diet containing 1% (w/w) L-canavanine sulfate, the SLE-like syndrome was reactivated.
Malinow et al (1984) reported that alfalfa seeds which were autoclaved for 2 hr contained no detectable canavanine. There were no symptoms of a syndrome resembling SLE in cynomolqus macaques that were fed autoclaved alfalfa seeds for up to 1 yr. These results supported the contention that canavanine was responsible for the adverse effects of alfalfa seeds and sprouts observed in monkeys.
The study of Malinow et al. followed established scientific protocols and had the appropriate and necessary controls-overall the evidence is substantial and convincing. On the other hand, extensive research in our laboratory has demonstrated that the rat is only somewhat sensitive to the adverse effects of canavanine and the mouse is extremely resistant. The question then is which of these mammals is the most appropriate test system for human comparison?

Alcocer-Varela et al (1985) demonstrated canavanine's dose-related effects in vitro on human immunoregulatory cells, which could explain the induction or exacerbation of SLE by alfalfa. Canavanine inhibited the generation of T-suppressor cells in human peripheral blood mononuclear cell cultures. Arginine had no inhibitory effect on this system, demonstrating the specificity of canavanine's inhibitory action on T cells. The abrogation of T suppressor cells was postulated by these investigators to be canavanine's mechanism of inducing the SLE-like syndrome, because other drugs capable of producing SLE also have the ability to inhibit T suppressor cell generation (Kirtland et al., 1980; Alarcon-Segovia and Palacios, 1982; Bluestein et al., 1979).

Another study of canavanine's effects on autoantibody production was conducted in autoimmune and normal mice (Prete, 1985). The results demonstrated that a canavanine-containing diet induced autoanitbodies in certain mouse strains and mediated renal damage with a significant increase in proteinuria. Susceptibility to canavanine's effects on the immune system appeared to be strain dependent.

Prete and Pedram (1985) reported that canavanine altered B-cell function in vitro and in vivo and speculated that an alteration in B-cell surface membrane properties in animals genetically susceptible to autoimmune disease may be the mechanism of action of canavanine-induced SLE. The authors suggested that canavanine exerted its effects through alteration of cell-cell interactions at surface receptor sites.

At this time, there is some controversey concerning which immunoregulatory cells, T-cells or B-cells, are affected by canavanine and which are responsible for canavanine-induced systemic lupus erythematosus. However, there is agreement that several mechanisms may be involved and that canavanine could have multiple effects on the immune system which may differ between species.

Clearly, there is sufficient evidence to believe that individuals suffering from SLE-like diseases should avoid the consumption of alfalfa sprouts and seeds, but what about the non-affected population.

Experiments conducted in my laboratory by Deborah Thomas, as part of her Ph.D. program, demonstrated that the white rat, a reasonable model for humans, shows considerable resistant to the deleterious effects of canavanine-only the newly developing neonatal rat is sensitive. Canavanine moves quickly to the liver where hepatic arginase catalyzes an efficient breakdown of this arginine antagonist. This metabolic catabolism coupled with urinary excretion resulted in a rapid drop in blood serum canavanine to an innocuous level before deterimental effects were manifested.

Serum elimination curves following intravenous or subcutaneous administration of canavanine established that canavanine was rapidly cleared from the serum of the animal.

Orally administered canavanine showed a bioavailability of only 43%. Therefore, most of the administered canavanine did not find its way into the bloodstream.

Dr. Thomas' investigations, however, demonstrated that repeated canavanine exposure was detrimental to both the neonatal and adult rat. It is germane that in order to achieve this pernicious effect, the rats were administered 3g/kg canavanine daily for 6 days. This is a high dose and would require the consumption of absurd amounts of alfalfa to provide comparable exposure. Nevertheless, the reported adverse effects of repeated canavanine consumption have been confirmed in our insectan studies with M. sexta.

IN SUMMARY, WITH THE EXCEPTION OF INDIVIDUALS CONCERNED ABOUT SLE-LIKE CONDITIONS, THE EVIDENCE SUPPORTS MY PERSONAL BELIEF THAT EVEN DAILY MAMMALIAN CONSUMPTION OF CANAVANINE VIA ALFALFA SPROUTS DOES NOT REPRESENT A SIGNIFICANT HEALTH HAZARD

part of this link was taken from the thesis of Dr. D.Thomas