Biologically-Guided Isolation of Natural Lead Antithyroid Drug from Medicago sativa L. Sprouts and Its Toxic Profile in Comparison with Propylthiouracil
Open Access
- 28 August 2020
- journal article
- research article
- Published by The Journal of Food and Drug Analysis (JFDA), Food and Drug Administration, Taiwan (TFDA) in Journal of Food and Drug Analysis
- Vol. 28 (3), 5-448
- https://doi.org/10.38212/2224-6614.1242
Abstract
Hyperthyroidism is a common endocrine disorder associated with increased risk of cardiovascular complications and mortality. Although antithyroid drugs (ATDs) are approved as first line option for many hyperthyroidism cases, including pregnancy and childhood, they exert significant toxic profile. Medicago sativa L. (alfalfa) also called “The father of all food” was among the diet consumed by mares that gave birth to foals with congenital hypothyroidism. Since, greenfeed was accused for the development of such condition, alfalfa may possess constituents with promising antithyroid potential that could be a valuable substitute for the conventional ATDs. The current work was designed to identify the most biologically active antithyroid phytoconstituent separated from alfalfa sprouts and comparing its antithyroid mechanism, efficacy and toxic profile to the standard ATD; propylthiouracil (PTU). The most biologically active solvent fractions from alfalfa sprouts extract were identified by in vitro screening for anti-thyroid peroxidase (TPO) activity, from which different phytoconstituents were separated and identified by interpretation of spectroscopic data. These compounds were then in vitro screened for anti-TPO and virtually screened via GLIDE XP docking into the crystal structures of the enzymes; bovine lactoperoxidase, as an alternative to TPO, and mammalian selenocysteine-dependent iodothyronine deiodinase (IDI), that are both uniquely dually prohibited by PTU. The compound that showed the least TPO IC50 and highest combined docking XP score was elected for comparing its antithyroid mechanism, efficacy, tendency to reverse hyperthyroidism-triggered complications and toxicity to PTU using L-thyroxine-induced hyperthyroidism model in rats. Seven compounds (1-7) were isolated from the most biologically active fraction, whilst, compounds (4-7) were reported for the first time from alfalfa sprouts. Compound 5 (apigenin) showed the least TPO IC50 and highest in-silico combined score, thus, apigenin was selected for further in-vivo investigations. Apigenin was found to more effectively interfere with type 1-IDI than with TPO in vivo. Apigenin therapy resulted in nearly euthyroid state, without incidence of hypothyroidism, thyroid hypertrophy, hepatotoxity or WBCs count reduction. In addition, apigenin, but not PTU, corrected hyperthyroidism-induced left ventricular hypertyrophy. Therefore, apigenin is a natural lead antithyroid drug that represents a possible safer alternative to conventional ATDsKeywords
This publication has 71 references indexed in Scilit:
- Antioxidant and Protective Effects ofBupleurum falcatumon the L-Thyroxine-Induced Hyperthyroidism in RatsEvidence-Based Complementary and Alternative Medicine, 2012
- The isolation of bioactive flavonoids from Jacaranda obtusifolia H. B. K. ssp. rhombifolia (G. F. W. Meijer) GentryActa Pharmaceutica, 2012
- Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical EndocrinologistsThyroid®, 2011
- Effects of Thyroid Dysfunction on Lipid ProfileThe Open Cardiovascular Medicine Journal, 2011
- Influence of Thyroid Hormones and Transforming Growth Factor-β1 on Cystatin C ConcentrationsJournal of International Medical Research, 2010
- Ethyl acetate extracts of alfalfa (Medicago sativa L.) sprouts inhibit lipopolysaccharide-induced inflammation in vitro and in vivoJournal of Biomedical Science, 2009
- The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR ExperimentsClinical Chemistry, 2009
- Cardiac hypertrophy and thyroid hormone signalingHeart Failure Reviews, 2009
- Effect of Low Thyroid Function on Cardiac Structure and Function in Spontaneously Hypertensive Heart Failure RatsJournal of Cardiac Failure, 2008
- Clinical Pharmacokinetics of Antithyroid DrugsClinical Pharmacokinetics, 1981