Mechanism for Inhibition of Thyroid Peroxidase by Leucomalachite Green
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- 作者：Daniel R. Doerge ; Hebron C. Chang ; Rao L. Divi ; and Mona I. Churchwell
- 刊名：Chemical Research in Toxicology
- 出版年：1998
- 出版时间：September 1998
- 年：1998
- 卷：11
- 期：9
- 页码：1098 - 1104
- 全文大小：96K
- 年卷期：v.11,no.9(September 1998)
- ISSN：1520-5010
文摘
The triphenylmethane dye, malachite green (MG), is used to treat and prevent fungal andparasitic infections in the aquaculture industry. It has been reported that the reducedmetabolite of MG, leucomalachite green (LMG), accumulates in the tissues of fish treated withMG. MG is structurally related to other triphenylmethane dyes (e.g., gentian violet andpararosaniline) that are carcinogenic in the liver, thyroid, and other organs of experimentalanimals. The ability of LMG to inhibit thyroid peroxidase (TPO), the enzyme that catalyzesthe iodination and coupling reactions required for thyroid hormone synthesis, was determinedin this study. LMG inhibited TPO-catalyzed tyrosine iodination (half-maximal inhibition atca. 10 
M). LMG also inhibited the TPO-catalyzed formation of thyroxine in low-iodine humangoiter thyroglobulin (half-maximal inhibition at ca. 10 M) using a model system that measuressimultaneous iodination and coupling. Direct inhibition of the coupling reaction by LMG wasshown using a coupling-only system containing chemically preiodinated thyroglobulin as thesubstrate. Incubation of LMG with TPO, iodide, and tyrosine in the presence of a H2O2-generating system yielded oxidation products that were identified by using on-line LC/APCI-MS as desmethyl LMG, 2desmethyl LMG, 3desmethyl LMG, MG, and MG N-oxide. Similarproducts from LMG were observed in incubations with TPO and H2O2 alone. These findingssuggest that the anti-thyroid effects (increased serum thyroid-stimulating hormone anddecreased serum thyroxine) observed in rats treated with LMG result from blockade of hormonesynthesis through alternate substrate inhibition and that chronic exposure could cause thyroidfollicular cell tumors through a hormonal mechanism. The observed TPO-catalyzed oxidativedemethylation of LMG to a primary arylamine also suggests a genotoxic mechanism for tumorformation is possible.
M). LMG also inhibited the TPO-catalyzed formation of thyroxine in low-iodine humangoiter thyroglobulin (half-maximal inhibition at ca. 10 M) using a model system that measuressimultaneous iodination and coupling. Direct inhibition of the coupling reaction by LMG wasshown using a coupling-only system containing chemically preiodinated thyroglobulin as thesubstrate. Incubation of LMG with TPO, iodide, and tyrosine in the presence of a H2O2-generating system yielded oxidation products that were identified by using on-line LC/APCI-MS as desmethyl LMG, 2desmethyl LMG, 3desmethyl LMG, MG, and MG N-oxide. Similarproducts from LMG were observed in incubations with TPO and H2O2 alone. These findingssuggest that the anti-thyroid effects (increased serum thyroid-stimulating hormone anddecreased serum thyroxine) observed in rats treated with LMG result from blockade of hormonesynthesis through alternate substrate inhibition and that chronic exposure could cause thyroidfollicular cell tumors through a hormonal mechanism. The observed TPO-catalyzed oxidativedemethylation of LMG to a primary arylamine also suggests a genotoxic mechanism for tumorformation is possible.