Increased glucuronidation of thyroid hormone in hexachlorobenzene-treated rats

Raaij, J.A.G.M. van; Kaptein, Ellen; Tj, Visser; Berg, K.J. van den

doi:10.1016/0006-2952(93)90136-k

Cited by 69 publications

(31 citation statements)

References 23 publications

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“…T 3 is purported to be glucuronidated by UGT2B2 (Beetstra et al, 1991;van Raaij et al, 1993;Visser et al, 1993b). This activity is increased by PCN (Hood and Klaassen, 2000); however, no elevation of UGT2B2 mRNA by PCN was demonstrated in this study.…”

Section: Vansell and Klaassencontrasting

confidence: 63%

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Vansell¹,

Klaassen²

2002

Drug Metab Dispos

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ABSTRACT:Treatment of rats with the microsomal enzyme inducers pregnenolone-16␣-carbonitrile (PCN), 3-methylcholanthrene (3-MC), and Aroclor 1254 [PCB (polychlorinated biphenyl)] has been shown to decrease circulating levels of thyroid hormones as well as increase microsomal glucuronidation of thyroxine (T 4 ). In addition, PCN increases triiodothyronine (T 3 ) uridine diphosphate glucuronosyltransferase (UGT) activity. Members of the UGT1A family are believed to glucuronidate T 4 , specifically UGT1A1 and UGT1A6, whereas the UGT2 family is believed to glucuronidate T 3 , namely UGT2B2. The purpose of this study was to determine whether the aforementioned microsomal enzyme inducers increase the mRNAs that encode these and other UGT enzymes in rat liver. Male Sprague-Dawley rats were fed a control diet or a diet containing PCN (1000 ppm), 3-MC (250 ppm), or PCB (100 ppm) for 7 days, at which time livers were collected. Increases in mRNA were detected by QuantiGene branched DNA signal amplification. A 3-fold increase in UGT1A1 mRNA was produced by PCN in addition to increases in UGT1A2 (4-fold) and UGT1A5 (2-fold) mRNA. PCN affected neither UGT2B2 nor any other UGT2B mRNA level. 3-MC and PCB increased UGT1A6 mRNA 6-and 4-fold, respectively. 3-MC and PCB each increased UGT1A7 mRNA 4-fold but did not significantly increase any other UGT mRNAs. These findings suggest that PCN enhances T 4 UGT activity by increased expression of UGT1A1 and that 3-MC and PCB enhance T 4 UGT activity by increased expression of UGT1A6. These findings also suggest that increased T 3 UGT activity produced by PCN is due to a mechanism other than increased transcription of UGT2B2, possibly increased UGT2B2 protein or induction of another UGT enzyme.

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Section: Vansell and Klaassencontrasting

confidence: 63%

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Vansell¹,

Klaassen²

2002

Drug Metab Dispos

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“…Drugs and xenobiotics that accelerate the metabolic clearance ofT4 by induction ofUGT isoenzymes include polychlorobiphenyls, dioxin, fibrates, phenobarbital, and other anticolvulsant drugs Beetstra et al, 1991;Visser et al, 1991aVisser et al, , 1993bSaito et al, 1991;De Sandro et al, 1991Barter and Klaassen, 1992a, 1992b: Van Raaij et al, 1993. The resultant decrease in serum T4 causes an increase in TSH secretion and, thus, a stimulation of thyroid activity.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work in our laboratory has suggested that at least three UGT isoenzymes are involved with the glucuronidation ofT4 and T3 in rat liver (Beetstra et al, 1991;Visser et al, 1991aVisser et al, , 1993aVisser et al, , 1993bVan Raaij et al, 1993). This was based on the following findings:…”

Section: Discussionmentioning

confidence: 99%

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats

Visser

Kaptein

Gijzel

et al. 1996

Endocr

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Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin, p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI-or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI-or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by

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“…Inhibition of the deiodinase enzymes can result in a decrease in T 3 available to elicit thyroid action at the tissue level (100). Conversely, deiodinase activity may increase in response to chemical exposure, either as a direct effect or in response to increased clearance of T 4 /T 3 by the chemical stimulation of glucuronidase or sulfatase enzymes (101,102). BruckerDavis (93) suggests that such increases in the metabolism and clearance of T 3 could result in a goiter as the thyroid gland increases production to maintain proper hormone levels.…”

Section: Xenobiotic Interference With the Thyroid Systemmentioning

confidence: 99%

A model of the development of the brain as a construct of the thyroid system.

Howdeshell

2002

Environ Health Perspect

333

237

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Thyroid hormone is essential for normal brain development. However, little is known about the molecular and cellular mechanisms that mediate thyroid hormone action on the developing brain or the developmental events selectively affected. Consequently, although a large number of environmental chemicals interfere with the thyroid system, there are few neurodevelopmental end points to recruit for toxicological studies. Therefore, my goal here is to review what is known about the relative timing of normal brain construction and thyroid system development, with special focus on the period of in utero development in humans and the comparable developmental period in laboratory rats. These data are presented as a timeline to aid in the identification of thyroid-sensitive end points in brain development and to highlight important data gaps. I discuss the known influence of certain synthetic chemicals on the thyroid system and include a brief review of the effects of developmental exposure to chemicals on thyroid system function. The relationship between the thyroid hormone and retinoic acid systems, as well as the thyroid hormone sensitivity of the developing cochlea, is also discussed.

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Increased glucuronidation of thyroid hormone in hexachlorobenzene-treated rats

Cited by 69 publications

References 23 publications

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats

A model of the development of the brain as a construct of the thyroid system.

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