title: A comparison of potency differences among thyroid peroxidase (TPO) inhibitors to induce developmental toxicity and other thyroid gland-linked toxicities in humans and rats.
abstract: The potencies of resorcinol, 6-propylthiouracil (PTU) and methimazole (MMI) for inducing developmental toxicity and neurotoxicity were compared in pregnant rats, regarded as valid model for human thyroid toxicity. Profound differences on maternal thyroid hormone levels (THs), maternal toxicity as well as developmental and neurotoxicity sequelae occurred. Resorcinol affected none of those end points. PTU and MMI caused significant effects. Therapy with either PTU or MMI during the first trimester of human pregnancy can cause reductions of maternal THs, accompanied by disruptions of prenatal development. Clinical MMI studies show sporadic evidence of teratogenic effects, with equivocal relation to thyroid peroxidase (TPO) inhibition. In recent decades no MMI associated prenatal toxicity has been reported, an outcome possibly related to carefully managed therapy. Orally administered resorcinol was rapidly absorbed, metabolized and excreted and was undetectable in the thyroid. In contrast, PTU or MMI accumulated. Resorcinol's potency to inhibit TPO was profoundly lower than that of PTU or MMI. Quantum chemical calculations may explain low resorcinol reactivity with TPO. Thus, distinctions in the target organ and the TPO inhibitory potency between these chemicals are likely contributing to different reductions of maternal THs levels and affecting the potency to cause developmental toxicity and neurotoxicity.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98, Kasugadenaka, Konohana-ku, Osaka, 554-8558, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Motonaga
authors.affiliation: Sumika Technoservice Co., 4-2-1, Takatsukasa, Takarazuka, Hyogo, 665-0051, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Ota
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98, Kasugadenaka, Konohana-ku, Osaka, 554-8558, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Odawara
authors.affiliation: Sumika Chemical Analysis Service, Ltd., 3-22-5, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Saito
authors.affiliation: Orbitox, International Toxicology Consultants, 7 Avenida Vista Grande #274, Santa Fe, NM, 87508, USA. Electronic address: orbitox@comcast.net.
authors.forename: Frank
authors.initials: F
authors.lastname: Welsch
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D006801:Humans; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008713:Methimazole / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology; D011247:Pregnancy; D011441:Propylthiouracil / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D012118:Resorcinols / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D018570:Risk Assessment; D013961:Thyroid Gland / Q000187:drug effects* / Q000201:enzymology; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D004791:Enzyme Inhibitors; D033862:Iron-Binding Proteins; D012118:Resorcinols; D013963:Thyroid Hormones; D008713:Methimazole; D011441:Propylthiouracil; C056658:TPO protein, human; D007453:Iodide Peroxidase; C031389:resorcinol
keywords: 6-Propylthiouracil (PTU); Developmental neurotoxicity; Developmental toxicity; Methimazole (MMI); Resorcinol; Thyroid peroxidase (TPO)