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Table of Contents | |
TOXIC CHEMICALS AND XENOBIOTICS
Eduardo Gaitan., M.D. and Robert C. Cooksey, M.S. University of
Mississippi School of Medicine and VA Medical Center, Jackson, MS 39216
SIMPLE GOITER AND AUTOIMMUNE THYROIDITIS (AT): ENVIRONMENTAL AND
GENETICS FACTORS.
The incidence of AT has steadily increased in the United States during the past
five decades and it has been attributed to excessive iodine intake. Prior to
iodine prophylaxis in 1924, the Appalachian was one of three areas with highest
goiter prevalence in the U.S. At present, Goiter, AT and Subclinical
Hypothyroidism are prevalent in the coal-rich Appalachian area, while these
conditions are absent in the nearby Inner Bluegrass region of central Kentucky.
Thus, the question is raised as to whether the same region-specific
environmental factors that cause goiter (i.e., organic and microbial water
pollutants) operate in genetically predisposed individuals (i.e., HLA-DR5
antigens) to trigger the pathogenic mechanism leading to AT. Recent findings in
western Colombia reinforce the hypothesis that endemic goiter and AT are
intimately related and that dietary iodine and genetic composition determine
their clinical, histological and autoimmune presentations. Furthermore, AT
develops after administration of polycyclic aromatic hydrocarbons (PAH) and
carbon tetrachloride to the BUF rat and of thyroglobulin with bacterial
lipopolysaccharide to "good responder" mice, which differ from
"poor responders" in their H-2 haplotype. Besides, organic goitrogens
(resorcinol, thiocyanates, disulfides) and potential "triggers" of the
autoimmune response (PAH and halogenated hydrocarbons) have been isolated from
coal and water supplies of endemic areas.
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Thyroid 1995 Jun;5(3):177-83 |
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Nongoitrous (type I) amiodarone-associated
thyrotoxicosis: evidence of follicular disruption in vitro and in vivo.
Brennan MD, Erickson DZ, Carney JA, Bahn RS
Department of Laboratory Medicine, Mayo Clinic and Foundation, Rochester,
Minnesota 55905, USA.
Treatment with the antiarrhythmic agent amiodarone results in alterations in
thyroid hormone metabolism, and can induce either hypothyroidism or
hyperthyroidism (amiodarone-associated thyrotoxicosis, AAT). AAT occurs in
patients both with and without preexisting goiter. In our study of the
nongoitrous variety, the effect in vitro of amiodarone treatment and of
concurrent treatment with potential inhibitors on thyroid cells (FRTL-5) was
assessed by measuring the release of radiolabeled chromium (51Cr). In
addition, thyroid histopathology was evaluated in autopsy specimens from six
amiodarone-treated patients who had no pretreatment evidence of thyroid
disease. Histopathologic examination revealed minimal or no evidence of
thyroid follicular damage in specimens from amiodarone-treated euthyroid
patients (n = 4). In contrast, moderate to severe follicular damage and
disruption were present in glands from patients with AAT (n = 2). Studies in
vitro showed amiodarone to be cytotoxic to thyroid cells; this effect was
inhibited by treatment with dexamethasone (10(-3) mmol) or perchlorate (2.5
micrograms/mL). In summary, we demonstrate evidence in vitro and in vivo of
amiodarone-induced thyroid follicular damage and disruption in specimens
from patients with nongoitrous AAT and in cultured normal thyroid cells. In
addition, we demonstrate inhibition of this effect following treatment in
vitro with dexamethasone or perchlorate. Our findings support the concept
that nongoitrous (type I) AAT results from direct drug toxicity with
disruption of thyroid follicles and subsequent release of preformed thyroid
hormone.
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Endocrinology 1994 May;134(5):2277-82 |
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Studies on the in vitro cytotoxic effect of amiodarone.
Chiovato L, Martino E, Tonacchera M, Santini F, Lapi P, Mammoli C,
Braverman LE, Pinchera A
Istituto di Endocrinologia, University of Pisa, Italy.
Amiodarone, a potent antiarrhythmic drug, contains 37.2% iodine by weight
and may induce either hypo- or hyperthyroidism. The high iodine content of
amiodarone may be responsible for both complications, but a cytotoxic effect
of the drug on the thyroid resulting in thyroiditis has been reported. In
the present study the cytotoxic effect of amiodarone was evaluated in three
culture systems with different biological properties: 1) a strain of rat
thyroid cells (FRTL-5 cells) that maintains most differentiated functions of
normal thyroid cells, including an active iodide pump, but an inability to
organify iodide; 2) a line of Chinese hamster ovary (CHO) fibroblasts; and
3) freshly prepared primary cultures of human thyroid follicles (hTF) that
trap and organify iodide. Cells were radiolabeled with 51Cr and incubated
for 24 h with medium alone, medium plus amiodarone (3.75-200 microM), medium
plus an iodinated radiographic contrast agent (sodium diatrizoate; 7.5-200
microM), or medium plus potassium iodide (7.5-300 microM). At concentrations
ranging from 75-200 microM, amiodarone induced a significant and
dose-dependent release of 51Cr in FRTL-5 cells. In contrast, diatrizoate or
KI had no cytotoxic effect on FRTL-5 cells. In the same molar
concentrations, amiodarone was also cytotoxic in CHO cells. In hTF, the
release of 51Cr produced by amiodarone occurred at a lower concentration
(37.5 vs. 75 microM) and was significantly greater than that in FRTL-5
cells. The cytotoxic effect of amiodarone in hTF was partially, but
significantly, reduced by methimazole, an inhibitor of iodide organification.
In the FRTL-5 cell culture system, amiodarone also produced a dramatic
inhibition of TSH-stimulated cell growth. This growth-inhibiting effect of
amiodarone was evident at low concentrations (3.75-7.5 mumol/liter) of the
drug, which did not produce significant cytotoxicity. In conclusion, 1)
amiodarone had a cytotoxic effect in CHO fibroblasts, a nonthyroid cell
line; 2) this cytotoxic effect occurred in thyroid cells independent of
their ability to organify iodide; 3) however, the toxic effect of amiodarone
was greater and occurred at a lower molar concentration in freshly prepared
human thyroid follicles that trap and organify iodide; and 4) in the latter
culture system, methimazole, an inhibitor of iodide organification,
partially, but significantly, reduced the cytotoxic effect of amiodarone.
These data suggest that thyroid cytotoxicity produced by amiodarone is
mainly due to a direct effect of the drug on thyroid cells, but excess
iodide released from the drug may contribute to its toxic action.
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