Cattle and goats in Australia lack the ability to totally degrade 3-hydroxy-4(1H)-pyridone, also known as 3,4-dihydroxy pyridine (3,4 DHP), the ruminal metabolite of mimosine, a toxic aminoacid present in the leguminous shrub Leucaena leucocephala. Ruminants in Hawaii have this capacity due to the presence of micro-organisms able to rapidly degrade the DHP. A mixed bacterial population capable of rapidly degrading DHP in vitro was isolated from a goat on the island of Maui. Cultures were grown anaerobically, without added sugars, in Medium 98-5 containing DHP. Cultures at a dilution of 10(-12) from the original rumen fluid were introduced into Townsville and further sub-cultured and multiplied in vitro in strict isolation at the Oonoonba Veterinary Laboratory, Townsville. Infusion of the culture into a goat and a steer fed a 100% leucaena diet resulted in cessation of DHP excretion in the urine. After 60 days the serum thyroxine levels and thyroid size were normal and there were no clinical signs of disease. The ability of the rumen fluid to degrade DHP in vitro showed that the bacteria had become established in the rumen. In the absence of any disease in the animals, clearance has been given for the wider use of these cultures in areas where leucaena is grown. The limited evidence suggests that the leucaena toxicity problem can be solved by the use of these introduced bacteria.

Successful transfer of DHP‐degrading bacteria from Hawaiian goats to Australian ruminants to overcome the toxicity of Leucaena

A reversible arrest point in the late G1 phase of the mammalian cell cycle.

Chemical constraints to the use of tropical legumes in animal nutrition

Those nonprotein amino acids found in food and fodder plants and known to be toxic to man and domestic animals are described. These include toxins from many legume genera including Lathyrus, from other higher plant families, from seaweeds, and from fungi. Some inhibit protein synthesis, while others are incorporated into proteins with toxic effects. Basic processes such as urea synthesis and neurotransmission may be disrupted. The probable roles of nonprotein amino acids in protecting plants against predators, pathogens, and competing plant species are considered. The need to learn more of the nutritive value of nontoxic nonprotein amino acids and to explore the potential of others either as drugs or as leads to drugs in human and veterinary medicine is emphasized.

Nonprotein amino acids of plants: significance in medicine, nutrition, and agriculture.

Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation

Mice fed a diet containing 1% (w/w) 3-hydroxy-4(1H)-pyridone (DHP) developed goitre even with a diet high in iodine whereas mimosine (0.5% w/w) did not produce goitre even with a low-iodine diet. Thyroid enlargement was apparent (measured morphometrically) by the 7th week and was advanced by the 11th week. Histologically the goitre was hyperplastic in type. No marked histological changes were found in other organs of mice fed DHP or any organs of mice fed mimosine, except for some atrophy of hair follicles. A single intragastric dose of DHP inhibited the uptake of 125I by the thyroid in the rat but an equivalent dose of mimosine did not. Evidence is presented that the inhibition occurs at the iodine binding step, as with methyl thiouracil, rather than at the iodide trapping step, as with thiocyanate. Chronic treatment of mice with DHP, as with 6-methyl thiouracil, increased the avidity of the thyroid in taking up 125I. The major conjugated form of DHP in mammals, DHP-3-O-glucuronide, was almost as effective a goitrogen as the unconjugated compound when given by mouth but considerably less active than the free form in the blood stream. It was concluded that DHP is a potent antithyroid compound of the thiouracil type with low general toxicity, since mammals can tolerate a level of intake sufficient to produce goitre in spite of iodine supplementation.

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The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats.

Lack of information on the feeding value and on the presence of deleterious substances in many species belonging to the genus Indigofera has limited the potential use of these species as feed and fodder legumes. To obtain such information, leaves and seeds of 46 accessions representing 19 species of Indigofera that had shown some agronomic value were incorporated into a semi-synthetic diet at 5% w/w (seed) or 20% w/w (forage). The diets were fed to groups of young rats for 4 weeks, and dry matter intakes and growth rates relative to control diets were measured. Selected organs were examined for any histological changes. Seed and forage samples were analysed for indospicine, a hepatotoxin, and for the presence of another potentially deleterious substance, 3-nitropropanoic acid. Thirteen of the accessions representing 8 species were readily eaten and did not depress growth rates relative to control feeds, and another 13 representing 10 species gave acceptable growth rates. Liveweight gains were less affected by forage diets than by those containing seeds. With the exception of those in rats fed on diets containing I. spicata and I. nigritana, the organs of all other rats were histologically normal. It is unlikely that the concentration of 3-nitropropanoic acid (0.5-3.4 mg g-1 dry matter) in any feed was high enough to cause any of the observed toxic signs. Indospicine was present in only 4 of the 23 species tested, including all accessions of I. spicata, and the concentration of indospicine was a good indicator of the toxicity of these feeds. It is concluded that accessions that had produced growth rates comparable to those of controls may be recommended as non-toxic feeds suitable for further testing.

Indigofera species with agronomic potential in the tropics. Rat toxicity studies

Acute biochemical changes in rat liver induced by the naturally occurring amino acid indospicine

Effect of indospicine on incorporation of L-arginine-14C into protein and transfer ribonucleic acid by cell-free systems from rat liver.

Mimosine, a plant amino acid which is toxic in mammals, was shown to be a potent inhibitor of incorporation of [3H]thymidine in mouse bone marrow cells in liquid culture (is greater than 70% inhibition at a concentration of 2 x 10(-4) M). To determine the parts of the molecule responsible for the inhibitory mechanism the effects of 13 chemically related compounds were examined in this system. The structural features necessary for inhibitory activity of the 4(1H)-pyridones were (1) the 3-hydroxyl-4-oxo function of the pyridone ring together with (2) an alpha-alanine or a 2-aminoethyl side chain. Compounds based on several other hydroxy heterocyclic functions were either weakly active or inactive. 3-Hydroxy-4(1H)-pyridone, the goitrogen to which mimosine is converted in ruminants, was only slightly inhibitory. These results are compared with published information on the effects of some of these compounds on other types of mammalian cells in vitro. The mouse bone marrow system in which inhibition of incorporation of [3H]thymidine is used as an index of cytotoxicity was shown to be sensitive and reproducible, and could be useful for structure-activity investigations of other cytotoxic compounds.

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M.P. Hegarty

Papers

The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats.

Indigofera species with agronomic potential in the tropics. Rat toxicity studies

Acute biochemical changes in rat liver induced by the naturally occurring amino acid indospicine

Effect of indospicine on incorporation of L-arginine-14C into protein and transfer ribonucleic acid by cell-free systems from rat liver.

Comparative toxicities of mimosine and some chemically related compounds to mouse bone marrow cells in liquid culture.