Canavanine

176.17400

176.17

218-728-4

3HZV514J4B

DTXSID5045041

Crystals from absolute alcohol

2925290090

134.45000

0.09430

Solid

1.61g/cm3

184 °C

431.2ºC at 760mmHg

214.6ºC

1.602

Insoluble in alcohol, ether, benzene

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 deg C.

3.18X10-8 mm Hg at 25 deg C (est)

Specific optical rotation: +7.9 deg at 20 °C/D (c = 3.2)

Henry's Law constant = 4.03X10-19 at 25 °C (est)

pKa1 = 2.10 (carboxylic); pKa2 = 9.31 (amine) (est)

133.3 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Crystals from ethanol, MP 180-182 °C. Soluble in water; practically insoluble in alcohol. Forms a monohydrochloride, MP 190 °C /DL-Canavanine/|Hydroxyl radical reaction rate constant = 1.24X10-10 cu cm/molecule-sec at 25 °C (est)

NONH for all modes of transport

3

20/21/22

36

ES7002000

Xn

Stable under recommended storage conditions.

P280

H302-H312-H332

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302: Harmful if swallowed [Warning Acute toxicity, oral]

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical, or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment, and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist, or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

IDENTIFICATION AND USE: L-canavanine is a solid. It is a potentially toxic antimetabolite of L-arginine that is stored by many leguminous plants. It has demonstrative antineoplastic activity against a number of animal-bearing carcinomas and cancer cell lines. L-canavanine has been used as an experimental medication. HUMAN EXPOSURE AND TOXICITY: L-Canavanine is a naturally occurring L-amino acid that interferes with L-arginine-utilizing enzymes owing to its structural analogy with this L-amino acid. In macrophages and polymorphonuclear leukocytes, which express inducible nitric oxide synthase (iNOS), L-canavanine is able to prevent the L-arginine-derived synthesis of nitric oxide (NO). L-canavanine exerts differential effects on human platelets in relation to the concentrations: at low levels, it exerts antiaggregating effects by actions independent of NOS inhibition, whereas, at high levels, it inhibits NO synthesis and does not exert antiaggregating effects. L-canavanine was cytotoxic to human peripheral blood mononuclear leucocytes (PBMCs) in culture. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. ANIMAL STUDIES: It was only slightly toxic to rats following a single sc injection: the LD50 was 5.9 +/- 1 8 g/kg in adult rats and 5.0 +/- 1.0 g/kg in 10-day-old rats. Repeated sc administration of canavanine resulted in more severe toxicity. Weight loss and alopecia were observed in rats given daily sc canavanine injections for 7 days. Food intake was decreased by 80% in adult rats subjected to this dosing regimen, but returned to normal after canavanine injections were terminated. Histological studies of tissues from adult rats treated with 3.0 g/kg canavanine daily for 6 days revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase levels were elevated following one sc injection of 2.0 g/kg canavanine; after three daily injections both serum enzymes were depleted. Elevations in serum glucose and urea nitrogen, and depletion of cholesterol, were observed. The most significant changes were severe attenuations of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity. Eighteen female mice were fed a diet containing 1.56% canavanine sulphate (1% base) and eighteen others were fed a control diet from day 84 to day 477 of age. Four g/d/mouse diet were fed from day 84 to day 164 of age and 5 g/d/mouse were fed thereafter. Only 6 of 10 canavanine-fed mice with copulatory plugs (vs 5 of 5 controls) carried any pups to 17d of gestation. Counts of corpora lutea, embryos and resorption sites indicate that these significant effects on pregnancy may have been due to failure of implantation. Only 50% of control mice and a full 89% of canavanine-fed mice survived to 477 days of age. These results indicate that canavanine may extend the life of mice, but interferes with their reproduction. Mutagenic activities of l-canavanine and metabolite l-canaline on Salmonella typhimurium TA100 and Bacillus subtilis h 17 rec+ & M 45 rec- were investigated in order to elucidate the mechanism of cytotoxicity of each compound. Both compounds and their metabolites obtained from rat liver homogenate did not cause base-pair substitutions and frameshift activities on DNA structure. Apparently, the compounds do not act on DNA directly, but other mechanisms, such as formation of l-canavanine-containing proteins, appear to influence DNA metabolism. Canavanine induced marked growth inhibition of the rat colon carcinoma.

The growth and development of final-stadium tobacco hornworm, manduca sexta (sphingidae) larvae fed a 2.5 mmole l-canavanine containing diet was markedly disrupted. Such canavanine-mediated disruption of larval growth was intensified greatly when these organisms were fed a canavanine-containing diet supplemented with a 1:10 molar ratio of l-arginine, l-citrulline, l-ornithine, or l-2,4-diaminobutyric acid; the larvae possess enhanced hemolymph volume (edema) and a significant mortality results from incomplete larval-pupal ecdysis.|The modulatory effects of a non-selective endothelin receptor antagonist, bosentan, were investigated together with those of relatively selective inducible nitric oxide synthase inhibitors, aminoguanidine and L-canavanine, on mesenteric blood flow decrease, liver and spleen injury elicited by endotoxemia. Swiss albino mice (20-40 g) were administered intraperitoneally bosentan (3, 10 or 30 mg/kg), aminoguanidine (15 mg/kg) or L-canavanine (20 or 100 mg/kg) 10 min before they received saline or Escherichia coli endotoxin (10 mg/kg). After 4 hr, the mice were anesthetized, mesenteric blood flow values were measured, spleen and liver weight/body weight ratios were determined and the organs were examined histopathologically. Endotoxin decreased mesenteric blood flow (mL/min), saline: 3.0 +/- 0.2; endotoxin: 2.2 +/- 0.2: n=10, p<0.05), increased the weight of liver (g per kg body weight, saline: 47.5 +/- 2.0; endotoxin: 60.8 +/- 1.9: n=10, p<0.05) and spleen (g per kg body weight, saline: 3.9 +/- 0.5; endotoxin: 8.6 +/- 0.9; n=10, p<0.01) while it inflicted significant histopathological injury to both organs. Bosentan was ineffective at 3 mg/kg but at 10 and 30 mg/kg doses, it abolished all the deleterious effects of endotoxin without exception. Aminoguanidine blocked most of the effects of endotoxin except those on spleen. In contrast, L-canavanine blocked only the endotoxin-induced increase in liver weight but itself increased spleen weight and failed to block any other effects of endotoxin. Thus, it can be speculated that the beneficial effects of aminoguanidine are produced largely by mechanisms other than selective inducible nitric oxide synthase inhibition since L-canavanine was not fully effective. The beneficial effects of endothelin inhibition by using bosentan in endotoxemia can be further exploited for the understanding and the therapy of sepsis-related syndromes.|The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 hr-1 over 6 hr) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.|The effects of L-canavanine and cadmium on the ribonucleoprotein constituents of HeLa S3 cells have been analyzed. Both chemicals induce a similar pattern of alterations in different RNP structures as well as in both RNA and protein synthesis. Pulse and chase autoradiographic experiments reveal that both canavanine and cadmium induce a preferential inhibition of nucleolar RNA synthesis and a slowdown in the transport or processing of nucleolar and extranucleolar RNA. Nucleoli become round and compact. Accumulation of perichromatin granules and fibrils occurs, there is a depletion of interchromatin fibrils, and nuclear formations appear which seem to be involved in the morphogenesis of perichromatin granules accumulated during the treatments. The appearance of clusters of 29- to 35-nm granules might be related with a deficient assembling of constituents of perichromatin granules. The effects of different inhibitors of the transcriptional processes on the accumulation of perichromatin granules suggest that these granules represent a particular subpopulation of hnRNP.|On the basis of several physiological properties of L-canavanine, we have tested the prediction that this analogue of arginine would enhance the cytotoxic effects of gamma-rays in mammalian cells. Using the human colonic tumor cell line, HT-29, time-dose studies were performed with log-phase cultures in order to determine conditions which maximize the incorporation of L-canavanine into cellular proteins while leaving a large fraction of the cells viable for subsequent gamma-ray survival measurements. At an input ratio of 2.5 (L-canavanine:arginine), the analogue exerted a cytostatic effect on the cells for at least 6 days following one cell division. Little cell killing (less than 20%) by clonogenicity was caused by L-canavanine during the first 12 hr of treatment of log-phase cells, even at a L-canavanine:arginine ratio of 20. A 24-hr exposure, however, produced an exponential decrease in survival as a function of L-canavanine concentration. The interaction between L-canavanine treatment and gamma-ray damage with respect to cell survival was examined under several conditions and times based on the above findings. Optimal enhancement of X-ray-induced cytotoxicity (assayed by loss of clonogenicity) was observed with a 48-hr exposure to the analogue at a L-canavanine:arginine ratio of 10. A marked increase in radiosensitivity was observed when L-canavanine was administered either before or after irradiation of the cells. In both protocols, enhancement was seen at all radiation doses. Together with our earlier findings showing the antitumor activity of L-canavanine in L1210 murine leukemia, these results suggest the potential usefulness of this amino acid analogue in the treatment of cancer.

LD50 Rat sc (10 day old) 5.0 +/- 1.0 g/kg|LD50 Rat sc (adult) 5.9 +/- 1 8 g/kg

/PLANTS/ L-canavanine inhibited the appearance of nitrate reductase in both root tips and mature root sections of corn (zea mays).

L-Canavanine, a basic amino acid, was isolated from jack beans (Canavalia ensiformis (L), family: Leguminosae). The compound constitutes about 1.5% of the dry weight of alfalfa seed and sprouts(1).|L-Canavanine was isolated and identified as the active principle in Astragalus roots that inhibited metamorphosis of the silkworm Bombyx mori.

L-Canavanine's production and use in biochemical research(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 17(SRC), determined from a structure estimation method(2), indicates that L-canavanine is expected to have very high mobility in soil(SRC). The estimated pKa values of L-canavanine are 2.10 and 9.31(3), indicating that this compound will exist as a zwitterion in the environment and zwitterions generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). L-Canavanine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 17(SRC), determined from a structure estimation method(2), indicates that L-canavanine is not expected to adsorb to suspended solids and sediment(SRC). Estimated pKa values of 2.10 and 9.31(3) indicates L-canavanine will exist as a zwitterion at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of -4.26(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), L-canavanine, which has an estimated vapor pressure of 3.2X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase L-canavanine may be removed from the air by wet and dry deposition(SRC). L-Canavanine does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

L-Canavanine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). L-Canavanine does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for L-canavanine(SRC), using an estimated log Kow of -4.26(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of L-canavanine can be estimated to be 17(SRC). According to a classification scheme(2), this estimated Koc value suggests that L-canavanine is expected to have very high mobility in soil. The estimated pKa values of 2.10 and 9.31(3) indicate that this compound will exist as a zwitterion in the environment and zwitterions generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The estimated pKa values of L-canavanine are 2.10 and 9.31(1), indicating that this compound will exist as a zwitterion at pH values of 5 to 9; therefore, volatilization from water surfaces is not expected to be an important fate process. L-Canavanine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-8 mm Hg(SRC), determined from a fragment constant method(2).

Occupational exposure to L-canavanine may occur through inhalation and dermal contact with this compound at workplaces where L-canavanine is produced or used. Limited monitoring data indicate that the general population may be exposed to L-canavanine via ingestion of food. (SRC)

/EXPL THER/ L-Canavanine, a selective inhibitor of inducible nitric oxide (NO) synthase, has beneficial effects on the circulatory failure of rats with endotoxin shock. To investigate the direct relationship between these beneficial effects and the inhibition of the formation of NO in response to L-canavanine in endotoxin shock in the rat, we detected changes in venous nitrosyl-hemoglobin (NO-hemoglobin) levels using an electron spin resonance (ESR) assay. Anesthetized rats were injected with lipopolysaccharide (10 mg/kg iv). 1 hr after the lipopolysaccharide injection, the rats were divided into four groups: a lipopolysaccharide group receiving 0.3 mL of saline hourly, an L-canavanine 10 or an L-canavanine 20 group receiving L-canavanine 10 or 20 mg/kg iv hourly, respectively, and an L-NAME group receiving NG-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg followed by 10 mg/kg iv hourly. A sham group received saline instead of lipopolysaccharide, and an L-canavanine group received L-canavanine 20 mg/kg iv hourly, 1 hr after the saline injection. At 5 hr after the lipopolysaccharide or saline injection, pressor responses to noradrenaline (1 ug/kg iv) were obtained. In the lipopolysaccharide group, lipopolysaccharide caused a progressive decrease in mean arterial pressure and an impairment of pressor responsiveness to noradrenaline. Administration of L-canavanine or L-NAME attenuated the endotoxin-induced hypotension and vascular hyporeactivity to noradrenaline. L-Canavanine did not alter mean arterial pressure and the pressor response to noradrenaline in the L-canavanine group. The endotoxin-induced increases in venous levels of NO-hemoglobin were significantly inhibited by L-canavanine or L-NAME. These data indicate that the beneficial hemodynamic effects of L-canavanine are associated with inhibition of the enhanced formation of NO by inducible NO synthase in a rat model of endotoxin shock. L-Canavanine is a potential agent in the treatment of endotoxin shock.|/EXPL THER/ The cardiovascular failure in sepsis may result from increased nitric oxide biosynthesis, through the diffuse expression of an inducible nitric oxide synthase. In such conditions, nitric oxide synthase inhibitors might be of therapeutic value, but detrimental side effects have been reported with their use, possibly related to the blockade of constitutive nitric oxide synthase. Therefore, the use of selective inhibitors of inducible nitric oxide synthase might be more suitable. The aim of this study was to evaluate the effects of L-canavanine, a potentially selective inhibitor of inducible nitric oxide synthase, in an animal model of septic shock. Anesthetized rats were challenged with 10 mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a 5 hr infusion of either L-canavanine (20 mg/hr/kg, n=15), nitro-L-arginine methyl ester (5 mg/hr/kg, n=13) or 0.9% NaCl (2 mL/hr/kg, n=21). Lipopolysaccharide induced a progressive fall in blood pressure and cardiac index, accompanied by a significant lactic acidosis and a marked rise in plasma nitrate. All these changes were significantly attenuated by L-canavanine, which also improved the tolerance of endotoxemic animals to acute episodes of hypovolemia. In addition, L-canavanine significantly increased survival of mice challenged with a lethal dose of lipopolysaccharide. In contrast to L-canavanine, nitro-L-arginine methyl ester increased blood pressure at the expense of a severe fall in cardiac index, while largely enhancing lactic acidosis. This agent did not improve survival of endotoxemic mice. In additional experiments, we found that the pressor effect of L-canavanine in advanced endotoxemia (4 hr) was reversed by L-arginine, confirming that it was related to nitric oxide synthase inhibition. In contrast, L-canavanine did not exert any influence on blood pressure in the very early stage (first hour) of endotoxemia or in the absence of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide synthase inhibition by this agent. In conclusion, L-canavanine produced beneficial hemodynamic and metabolic effects and improved survival in rodent endotoxic shock. The actions of L-canavanine were associated with a selective inhibition of inducible nitric oxide synthase and were in marked contrast to the deleterious consequences of nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, in similar conditions.|/EXPL THER/ Administration of lipopolysaccharide to anesthetised rats produced a reduction in mean arterial pressure, an increase in heart rate, and death at 4-6 hr. Intravenous infusion of NG-nitro-L-arginine methyl ester (50 mg/kg), an inhibitor of constitutive and inducible nitric oxide (NO) synthase, 60 min after challenge with lipopolysaccharide, caused an immediate increase in blood pressure followed by a precipitous fall in pressure, and death. In contrast, intravenous infusion of L-canavanine (100 mg/kg), reported to be a selective inhibitor of inducible NO synthase in vitro, 60 min and 180 min after lipopolysaccharide challenge, produced an increase in mean arterial pressure and reversed the lipopolysaccharide induced hypotension. However, in lipopolysaccharide challenged animals protected from hypotension by administration of L-canavanine (60 min post challenge), intravenous infusion of NG-nitro-L-arginine methyl ester at 180 min post challenge caused an immediate rise in mean arterial pressure, followed by a rapid fall in blood pressure and heart rate, and sudden death. In contrast, a second dose of L-canavanine at 180 min post challenge maintained blood pressure for the duration of the experiment. These findings indicate that inhibition of both constitutive and inducible NO synthase during endotoxemia is lethal. However, the use of a selective inhibitor of inducible NO synthase restores mean arterial pressure to baseline, and offers a therapeutic approach to managing hypotension in shock.|/EXPL THER/ There is a clear need for agents with novel mechanisms of action to provide new therapeutic approaches for the treatment of pancreatic cancer. Owing to its structural similarity to L-arginine, L-canavanine, the beta-oxa-analog of L-arginine, is a substrate for arginyl tRNA synthetase and is incorporated into nascent proteins in place of L-arginine. Although L-arginine and L-canavanine are structurally similar, the oxyguanidino group of L-canavanine is significantly less basic than the guanidino group of L-arginine. Consequently, L-canavanyl proteins lack the capacity to form crucial ionic interactions, resulting in altered protein structure and function, which leads to cellular death. Since L-canavanine is selectively sequestered by the pancreas, it may be especially useful as an adjuvant therapy in the treatment of pancreatic cancer. This novel mechanism of cytotoxicity forms the basis for the anticancer activity of L-canavanine and thus, arginyl tRNA synthetase may represent a novel target for the development of such therapeutic agents.|For more Therapeutic Uses (Complete) data for (L)-CANAVANINE (8 total), please visit the HSDB record page.

The toxicity of L-canavanine was investigated because of its demonstrated potential as an antitumor drug. This natural product was only slightly toxic to Sprague-Dawley rats following a single sc injection: the LD50 was 5.9 +/- 1 8 g/kg in adult rats and 5.0 +/- 1.0 g/kg in 10-day-old rats. Following a single dose of 2.0 g/kg, the systemic clearance value for canavanine in adult rats was 0.114 liter/hr, the volume of distribution at steady state was 0.154 liter, and the half-life was 1.56 hr. Forty-eight percent of the dose was excreted unaltered in the urine following an iv injection, and 16% of a sc dose was recovered in the urine. Bioavailability of a 2.0 g/kg sc dose was 72%. Single oral doses of canavanine were less toxic to adult rats than sc injections. Bioavailability of a 2.0 g/kg po dose was 43%, and only 1% of the administered canavanine was recovered in the urine. Twenty-one percent of the administered canavanine remained in the gastrointestinal tract 24 hr after an oral dose. Less than 1% of a 2.0 g/kg dose of L-[guanidinooxy-(14)C]canavanine was incorporated into the proteins of adult and neonatal rats 4 or 24 hr following administration. Repeated sc administration of canavanine resulted in more severe toxicity. Weight loss and alopecia were observed in rats given daily sc canavanine injections for 7 days. Food intake was decreased by 80% in adult rats subjected to this dosing regimen, but returned to normal after canavanine injections were terminated. Histological studies of tissues from adult rats treated with 3.0 g/kg canavanine daily for 6 days revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase levels were elevated following one sc injection of 2.0 g/kg canavanine; after three daily injections both serum enzymes were depleted. Elevations in serum glucose and urea nitrogen, and depletion of cholesterol, were observed. The most significant changes were severe attenuations of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity.

L-Canavanine (CAV) is an arginine (ARG) analog isolated from the jack bean, Canavalia ensiformis. CAV becomes incorporated into cellular proteins of MIA PaCa-2 human pancreatic cancer cells and the aberrant, canavanyl proteins are not preferentially degraded. Hydrolytic cleavage of CAV to canaline (CAN) and urea is mediated by arginase. CAN is a potent metabolite that inactivates vitamin B6-containing enzymes and may inhibit cell growth. To determine the presence of arginase and its specificity for ARG and CAV in MIA PaCa-2 cells, a radiometric assay, which quantifies the (14)C released from the hydrolytic cleavage of L-[guanidino-(14)C]ARG or L-[guanidinooxy-(14)C]CAV mediated by arginase, was employed. Insignificant amounts of (14)CO2 were released when cells were exposed to [(14)C]CAV or to [(14)C]ARG. Pancreatic cancer cells secrete a negligible amount of arginase. Cytotoxic effects of CAN and CAV were compared on cells exposed to varying concentrations of ARG. These studies provide evidence that CAV's cytotoxic effects on MIA PaCa-2 cells cannot be attributed to conversion to the active metabolite CAN. A slower and decreased hydrolysis of CAV by arginase allows CAV to persist and increases its chances of incorporating into proteins in these cells. Lack of considerable amounts of arginase in the pancreas makes CAV a worthy candidate for further studies in pancreatic cancer.|L-Canavanine and its arginase-catalyzed metabolite, L-canaline, are two novel anticancer agents in development. Since the immunotoxic evaluation of agents in development is a critical component of the drug development process, the antiproliferative effects of L-canavanine and L-canaline were evaluated in vitro. Both L-canavanine and L-canaline were cytotoxic to peripheral blood mononucleocytes (PBMCs) in culture. Additionally, the mononucleocytes were concurrently exposed to either L-canavanine or L-canaline and each one of a series of compounds that may act as metabolic inhibitors of the action of L-canavanine and L-canaline (L-arginine, L-ornithine, D-arginine, L-lysine, L-homoarginine, putrescine, L-omega-nitro arginine methyl ester, and L-citrulline). The capacity of these compounds to overcome the cytotoxic effects of L-canavanine or L-canaline was assessed in order to provide insight into the biochemical mechanisms that may underlie the toxicity of these two novel anticancer agents. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. The elucidation of the biochemical mechanisms associated with the effects of L-canavanine and L-canaline on lymphoproliferation may be useful for maximizing the therapeutic effectiveness and minimizing the toxicity of these novel anticancer agents.|The metabolism of L-canavanine, a nonprotein amino acid with significant antitumor effects, was investigated. L-Canavanine, provided at 2.0 g/kg, was supplemented with 5 uCi of L-[guanidinooxy-(14)C]canavanine (58 uCi/mumol) and administered iv, sc, or orally to female Sprague-Dawley rats weighing approximately 200 g. 14C recovery in the urine at 24 hr was 83, 68, or 61%, respectively, of the administered dose. Another 5-8% of the (14)C was expired as (14)CO2. The gastrointestinal tract contained 21% of orally administered (14)C. Serum, feces, tissues, and de novo synthesized proteins only accounted for a few percent of the original dose by any administrative route. Analysis of the (14)C-containing urinary metabolites revealed that [(14)C] urea accounted for 88% of the urinary radioactivity for an iv injection, 75% for sc administration, and 50% following an oral dose. By all routes of administration, [(14)C]guanidine represented 5% of the radioactivity in the urine and [(14)C]guanidinoacetic acid accounted for 2%. Serum and urine amino acid analysis showed a markedly elevated ornithine level. Basic amino acids such as histidine, lysine, and arginine were also higher in the urine. Plasma ammonia levels were determined following oral canavanine doses of 1.0, 2.0, and 4.0 g/kg. A rapid but transient elevation in plasma ammonia was observed only at the 4.0 g/kg dose. This indicates that elevated plasma ammonia is not a likely cause of canavanine toxicity at the drug concentrations used in this study.|It was observed previously that hydroxyguanidine is formed in the reaction of canavanine(2-amino-4-guanidinooxybutanoate) with amino acid oxidases. The present work shows that hydroxyguanidine is formed by a nonenzymatic beta,gamma-elimination reaction following enzymatic oxidation at the alpha-C and that the abstraction of the beta-H is general-base catalyzed. The elimination reaction requires the presence in the alpha-position of an anion-stabilizing group--the protonated imino group (iminium ion group) or the carbonyl group. The iminium ion group is more activating than the carbonyl group. Elimination is further facilitated by protonation of the guanidinooxy group. The other product formed in the elimination reaction was identified as vinylglyoxylate (2-oxo-3-butenoate), a very highly electrophilic substance. The product resulting from hydrolysis following oxidation was identified as alpha-keto-gamma-guanidinooxybutyrate (ketocanavanine). The ratio of hydroxyguanidine to ketocanavanine depended upon the concentration and degree of basicity of the basic catalyst and on pH. In the presence of semicarbazide, the elimination reaction was prevented because the imino group in the semicarbazone derivative of ketocanavanine is not significantly protonated. Incubation of canavanine with 5'-deoxypyridoxal also yielded hydroxyguanidine. Since the elimination reactions take place under mild conditions, they may occur in vivo following oxidation at the alpha-C of L-canavanine (ingested or formed endogenously) or of other amino acids with a good leaving group in the gamma-position (e.g., S-adenosylmethionine, methionine sulfoximine, homocyst(e)ine, or cysteine-homocysteine mixed disulfide) by an L-amino acid oxidase, a transaminase, or a dehydrogenase. Therefore, vinylglyoxylate may be a normal metabolite in mammals which at elevated concentrations may contribute to the in vivo toxicity of canavanine and of some of the other above-mentioned amino acids.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ For the past 2 decades there has been vigorous disagreement over the purported toxicity of Hedysarum alpinum seeds, and whether the consumption of such seeds was a factor in the 1992 death of Chris McCandless, the subject of the book Into the Wild. Our objective was to confirm or disprove the presence of L-canavanine (a nonprotein amino acid known to induce systemic lupuslike symptoms in humans) in H. alpinum seeds. Liquid chromatography-tandem mass spectrometry analysis of H. alpinum seeds was performed. Our analysis confirmed the presence of L-canavanine in H. alpinum seeds and demonstrated that it is a significant component of the seeds, with a concentration of 1.2% (weight/weight), roughly half of that found in Canavalia ensiformis. The data led us to conclude it is highly likely that the consumption of H alpinum seeds contributed to the death of Chris McCandless.|/ALTERNATIVE and IN VITRO TESTS/ L-Canavanine and its arginase-catalyzed metabolite, L-canaline, are two novel anticancer agents in development. Since the immunotoxic evaluation of agents in development is a critical component of the drug development process, the antiproliferative effects of L-canavanine and L-canaline were evaluated in vitro. Both L-canavanine and L-canaline were cytotoxic to peripheral blood mononucleocytes (PBMCs) in culture. Additionally, the mononucleocytes were concurrently exposed to either L-canavanine or L-canaline and each one of a series of compounds that may act as metabolic inhibitors of the action of L-canavanine and L-canaline (L-arginine, L-ornithine, D-arginine, L-lysine, L-homoarginine, putrescine, L-omega-nitro arginine methyl ester, and L-citrulline). The capacity of these compounds to overcome the cytotoxic effects of L-canavanine or L-canaline was assessed in order to provide insight into the biochemical mechanisms that may underlie the toxicity of these two novel anticancer agents. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. The elucidation of the biochemical mechanisms associated with the effects of L-canavanine and L-canaline on lymphoproliferation may be useful for maximizing the therapeutic effectiveness and minimizing the toxicity of these novel anticancer agents.|/ALTERNATIVE and IN VITRO TESTS/ L-Canavanine (CAV) is a higher plant nonprotein amino acid and a potent L-arginine antimetabolite. CAV can inhibit the proliferation of tumor cells in vitro and in vivo, but little is known regarding the molecular mechanisms mediating these effects. We demonstrated that the treatment of human lung adenocarcinoma A549 cells with CAV caused growth inhibition; G1 phase arrest is accompanied by accumulation of an incompletely phosphorylated form of the retinoblastoma protein, whose phosphorylation is necessary for cell cycle progression from G1 to S phase. In addition, CAV induces the expression of p53 and subsequent expression of a cyclin-dependent kinase inhibitor, p21/WAF1. The p53-dependent induction of p21/WAF1 and the following dephosphorylation of the retinoblastoma protein by CAV could account for the observed CAV-mediated G1 phase arrest.|/ALTERNATIVE and IN VITRO TESTS/ L-Canavanine (CAV) is an arginine (ARG) analog isolated from the jack bean, Canavalia ensiformis. CAV becomes incorporated into cellular proteins of MIA PaCa-2 human pancreatic cancer cells and the aberrant, canavanyl proteins are not preferentially degraded. Hydrolytic cleavage of CAV to canaline (CAN) and urea is mediated by arginase. CAN is a potent metabolite that inactivates vitamin B6-containing enzymes and may inhibit cell growth. To determine the presence of arginase and its specificity for ARG and CAV in MIA PaCa-2 cells, a radiometric assay, which quantifies the (14)C released from the hydrolytic cleavage of L-[guanidino-(14)C]ARG or L-[guanidinooxy-(14)C]CAV mediated by arginase, was employed. Insignificant amounts of (14)CO2 were released when cells were exposed to [(14)C]CAV or to [(14)C]ARG. Pancreatic cancer cells secrete a negligible amount of arginase. Cytotoxic effects of CAN and CAV were compared on cells exposed to varying concentrations of ARG. These studies provide evidence that CAV's cytotoxic effects on MIA PaCa-2 cells cannot be attributed to conversion to the active metabolite CAN. A slower and decreased hydrolysis of CAV by arginase allows CAV to persist and increases its chances of incorporating into proteins in these cells. Lack of considerable amounts of arginase in the pancreas makes CAV a worthy candidate for further studies in pancreatic cancer.|For more Human Toxicity Excerpts (Complete) data for (L)-CANAVANINE (7 total), please visit the HSDB record page.

Canavanine

L-Homoserine, O-[(aminoiminomethyl)amino]-, sulfate (1:1): INACTIVE|L-Canavanine, a potentially toxic antimetabolite of L-arginine that is stored by many leguminous plants, has demonstrative antineoplastic activity against a number of animal-bearing carcinomas and cancer cell lines. This investigation evaluated the natural abundance of this anti-cancer compound in commercially available sprouts, and in ten varieties of the seed of alfalfa, Medicago sativa (L.). Canavanine abundance in commercially grown sprouts varied according to the source; the young plant stored appreciable canavanine that ranged from 1.3 to 2.4% of the dry matter. Alfalfa seeds were also rich in this nonprotein amino acid as the canavanine content varied from 1.4 to 1.8% of the dry matter. On average, the tested seeds contained 1.54 =/- 0.03% canavanine. Alfalfa seed canavanine content was comparable to the levels found in the seeds of representative members of the genus Canavalia, which are amongst the more abundance sources of this antimetabolite.

The major stored nitrogen compound in alfalfa seeds is canavanine. To identify this nonprotein amino acid from seed extract and sprout water, a qualitative micro-thin-layer chromatography method was developed. Successful separation and identification was achieved using microsilica plates, a 70:30 ethyl alcohol-water solvent system, and 1% ammonium disodium pentacyanoammineferrate II for color development. This quick method was used to identify canavanine (sensitivity 50 microg) from irradiated and nonirradiated alfalfa and clover seed extracts and alfalfa sprout water. Broccoli and radish seed extracts were negative for canavanine. This simple method is useful to track the release and decrease of canavanine in the sprout water.|The amino acid canavanine is a potentially toxic constituent of leguminous seeds. The aim of the present study was to determine the ability of different processing methods to reduce canavanine in sword beans (Canavalia gladiata). For this purpose a method for the detection and quantification of canavanine was developed using reversed-phase high-performance liquid chromatography of the dabsylated derivatives. The recovery of canavanine using this method was 88-91%. Optimum extraction of canavanine from raw and processed beans was obtained by addition of hot water prior to overnight soaking. The results obtained with this method agree well with previously published values for raw seeds. The method is sensitive, specific and can successfully be applied to the detection of canavanine in legumes. Overnight soaking and boiling in excess water followed by decanting gave the most pronounced reduction in canavanine content (around 50%), followed by boiling and decanting excess water (34%). Roasting as used in this study and autoclaving were less effective in reducing the canavanine content.