Phytochemicals: the good, the bad and the ugly?

Phytochemicals are constitutive metabolites that enable plants to overcome temporary or continuous threats integral to their environment, while also controlling essential functions of growth and reproduction. All of these roles are generally advantageous to the producing organisms but the inherent biological activity of such constituents often causes dramatic adverse consequences in other organisms that may be exposed to them. Nevertheless, such effects may be the essential indicator of desirable properties, such as therapeutic potential, especially when the mechanism of bioactivity can be delineated. Careful observation of cause and effect, followed by a coordinated approach to identify the responsible entities, has proved extremely fruitful in discovering roles for phytochemical constituents. The process is illustrated by selected examples of plants poisonous to animals and include the steroidal alkaloid toxin of Veratrum californicum (Western false hellebore), piperidine alkaloids of Lupinus species (lupines), and polyhydroxy indolizidine, pyrrolizidine and nortropane alkaloids of Astragalus and Oxytropis species (locoweeds), Castanospermum australe (Moreton Bay chestnut) and Ipomoea species (morning glories).

Comparative toxicosis of sodium selenite and selenomethionine in lambs.

Excess consumption of selenium (Se) accumulator plants can result in selenium intoxication. The objective of the study reported here was to compare the acute toxicosis caused by organic selenium (selenomethionine) found in plants with that caused by the supplemental, inorganic form of selenium (sodium selenite). Lambs were orally administered a single dose of selenium as either sodium selenite or selenomethionine and were monitored for 7 days, after which they were euthanized and necropsied. Twelve randomly assigned treatment groups consisted of animals given 0, 1, 2, 3, or 4 mg of Se/kg of body weight as sodium selenite, or 0, 1, 2, 3, 4, 6, or 8 mg of Se/kg as selenomethionine. Sodium selenite at dosages of 2, 3, and 4 mg/kg, as well as selenomethionine at dosages of 4, 6, and 8 mg/kg resulted in tachypnea and/or respiratory distress following minimal exercise. Severity and time to recovery varied, and were dose dependent. Major histopathologic findings in animals of the high-dose groups included multifocal myocardial necrosis and pulmonary alveolar vasculitis with pulmonary edema and hemorrhage. Analysis of liver, kidney cortex, heart, blood, and serum revealed linear, dose-dependent increases in selenium concentration. However, tissue selenium concentration in selenomethionine-treated lambs were significantly greater than that in lambs treated with equivalent doses of sodium selenite. To estimate the oxidative effects of these selenium compounds in vivo, liver vitamin E concentration also was measured. Sodium selenite, but not selenomethionine administration resulted in decreased liver vitamin E concentration. Results of this study indicate that the chemical form of the ingested Se must be known to adequately interpret tissue, blood, and serum Se concentrations.

Evaluation of the respiratory elimination kinetics of selenium after oral administration in sheep.

OBJECTIVE: To evaluate the respiratory excretion and elimination kinetics of organic and inorganic selenium after oral administration in sheep. ANIMALS: 38 crossbred sheep. PROCEDURES: Selenium was administered PO to sheep as a single dose of 0, 1, 2, 3, or 4 mg/kg as sodium selenite or selenomethionine. Expired air was collected and analyzed from all sheep at 4, 8, and 16 hours after administration. RESULTS: Clinical signs consistent with selenium intoxication were seen in treatment groups given sodium selenite but not in treatment groups given the equivalent amount of selenium as selenomethionine. However, a distinct garlic-like odor was evident in the breath of all sheep receiving 2 to 4 mg of selenium/kg. The intensity of odor in the breath did not correlate with clinical signs in affected animals receiving sodium selenite treatment. CONCLUSIONS AND CLINICAL RELEVANCE: The concentration of selenium in expired air was greater in sheep receiving selenium as selenomethionine than sodium selenite. The concentration of selenium in expired air from sheep receiving high doses of selenium (3 and 4 mg of selenium/kg) was larger and selenium was expired for a longer duration than the concentration of selenium in expired air from sheep receiving low doses of selenium (1 and 2 mg of selenium/kg).

Comparison of plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis or clinically normal calves.

OBJECTIVE: To compare plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis and cattle that had given birth to clinically normal calves and determine whether the difference in outcome was associated with differences in plasma disposition of anagyrine. ANIMALS: 6 cows that had given birth to calves with arthrogryposis and 6 cows that had given birth to clinically normal calves after being similarly exposed to lupine during pregnancy. PROCEDURES: Dried lupine (2 g/kg) was administered via gavage. Blood samples were collected before and at various time points for 48 hours after lupine administration. Anagyrine, 5,6-dehydrolupanine, and lupanine concentrations in plasma were measured by use of gas chromatography. Plasma alkaloid concentration versus time curves were generated for each alkaloid, and pharmacokinetic parameters were determined for each cow. RESULTS: No significant differences in area under the plasma concentration versus time curve, maximum plasma concentration, time to reach maximum plasma concentration, and mean residence time for the 3 alkaloids were found between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Because no differences were found in plasma disposition of anagyrine following lupine challenge between cattle that had given birth to calves with arthrogryposis and those that had not, our findings do not support the hypothesis that between-cow differences in plasma disposition of anagyrine account for within-herd differences in risk for lupine-induced arthrogryposis.

Biomedical applications of poisonous plant research.

Research designed to isolate and identify the bioactive compounds responsible for the toxicity of plants to livestock that graze them has been extremely successful. The knowledge gained has been used to design management techniques to prevent economic losses, predict potential outbreaks of poisoning, and treat affected animals. The availability of these compounds in pure form has now provided scientists with tools to develop animal models for human diseases, study modes of action at the molecular level, and apply such knowledge to the development of potential drug candidates for the treatment of a number of genetic and infectious conditions. These advances are illustrated by specific examples of biomedical applications of the toxins of Veratrum californicum (western false hellebore), Lupinus species (lupines), and Astragalus and Oxytropis species (locoweeds).

Polyhydroxy alkaloids: chromatographic analysis.

Polyhydroxy alkaloids are a burgeoning category of natural products that encompass several structural types and generally exhibit potent activity as inhibitors of glycosidases. As presently defined the group consists of monocyclic or bicyclic aLkaloids of the pyrrolidine, piperidine, pyrrolizidine, indolizidine and tropane classes, bearing two or more hydroxyl groups. These structural features render the compounds highly water soluble and frequently quite insoluble in non-hydroxylic solvents, so that their isolation and analysis by chromatographic means are consequently difficult. This problem is further confounded by the lack of a chromophore which would permit their detection by UV absorption. This review presents chromatographic techniques that have been successfully applied to the problem of isolating, purifying, detecting and analyzing polyhydroxy alkaloids.

Preparation of tetrahydroagathic acid: a serum metabolite of isocupressic acid, a cattle abortifacient in ponderosa pine.

Isocupressic acid (1) was used to synthetically prepare a mixture of (8S,13R,S)-labda-15,19-dioic acid (tetrahydroagathic acid) (5) via a two-step oxidation procedure followed by hydrogenation of the double bonds at C13 and C8. Reduction of the C8,17 double bond was stereospecific producing only the 8S isomer and confirmed by the nOe interaction between the resulting C17 and C20 methyl groups. The 13R and 13S isomers of 5 were separated and analyzed by HPLC/MS, and (13S)-tetrahydroagathic acid was isolated and identified by comparison to a standard prepared by hydrogenation of naturally occurring (13S)-dihydroagathic acid (4). (13R,S)-dihydroagathic acid was prepared by selective sodium metal-catalyzed hydrogenation of the C13,14 allylic double bond of agathic acid (3). The prepared compounds were then used as standards to confirm the presence of 4 and 5 and their respective 13R and 13S isomers in bovine serum samples. Tetrahydroagathic acid was shown to be the only metabolite detected in serum samples taken from a suspected cattle abortion case submitted for diagnosis; and, thus, 5 could be a valuable diagnostic marker for pine needle-induced abortions.