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The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats
Abstract:
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.
Insights
3-hydroxy-4(1H)-pyridone (DHP) is a potent antithyroid compound that causes goiter in mice by inhibiting iodine binding. DHP exhibits low general toxicity, even when iodine intake is high.
Area of Science:
- Endocrinology
- Toxicology
- Pharmacology
Background:
- Goiter, or thyroid enlargement, can result from various dietary factors.
- Mimosine and its metabolite 3-hydroxy-4(1H)-pyridone (DHP) are plant-derived compounds with potential biological effects.
Purpose of the Study:
- To investigate the goitrogenic and antithyroid effects of DHP and mimosine in animal models.
- To elucidate the mechanism of action of DHP on thyroid function.
Main Methods:
- Administration of DHP and mimosine to mice and rats via diet or intragastric doses.
- Morphometric and histological analysis of thyroid glands.
- Radioiodine (125I) uptake studies in rats and mice.
- Investigation of DHP-3-O-glucuronide activity.
Main Results:
- Mice fed DHP developed hyperplastic goiter, evident by week 7 and advanced by week 11, even with high iodine intake.
- Mimosine did not induce goiter, even on a low-iodine diet.
- DHP inhibited thyroidal 125I uptake in rats by interfering with the iodine binding step, similar to methyl thiouracil.
- Chronic DHP treatment increased thyroidal 125I uptake avidity in mice.
- DHP-3-O-glucuronide was a less potent goitrogen than DHP when administered orally or systemically.
Conclusions:
- DHP is a potent antithyroid compound of the thiouracil type.
- DHP's mechanism involves inhibition of iodine binding to thyroid hormones.
- DHP demonstrates low general toxicity, with mammals tolerating goitrogenic levels even with iodine supplementation.
