Activities of UDP-glucuronyltransferase, beta-glucuronidase and deiodinase types I and II in hyper- and hypothyroid rats

Abstract

We have investigated the hypothesis that uridine 5 -diphosphate (UDP)-glucuronyltransferases (UGTs) and -glucuronidase are jointly involved in a mechanism for the storage and mobilization of iodothyronine metabolites in liver, kidney, heart and brain. Specifically, we predicted UGT activities to decrease and increase respectively, and -glucuronidase activity to increase and decrease respectively in hypo-and hyperthyroidism. To this end we have studied the effects of thyroid status on the activities of different enzymes involved in thyroid hormone metabolism in liver, kidney, heart and brain from adult rats with experimentally induced hypo-and hyperthyroidism. We used whole organ homogenates to determine the specific enzyme activities of phenol-and androsteron-UGT, -glucuronidase, as well as iodothyronine deiodinase types I and II. Deiodinase type I activities in liver and kidney were decreased in hypothyroid animals and, in liver only, increased in hyperthyroidism. Deiodinase type II activity was increased in hyperthyroid rat kidney only. Interestingly, in the heart, deiodinase type I-specific activity was increased fourfold, although the increase was not statistically significant. Cardiac deiodinase type I activity was detectable but not sensitive to thyroid status. Hepatic phenol-UGT as well as androsteron-UGT activities were decreased in hypothyroid rats, with specific androsteron-UGT activities two to three orders of magnitude lower than phenol-UGT activities. Both UGT isozymes were well above detection limits in heart, but appeared to be insensitive to thyroid status. In contrast, cardiac -glucuronidase activity decreased in hypothyroid tissue, whereas the activity of this enzyme in the other organs investigated did not change significantly.In summary, cardiac -glucuronidase, albeit in low levels, and hepatic phenol-UGT activities were responsive only to experimental hypothyroidism. Although a high basal activity of the pleiotropic -glucuronidase masking subtle activity changes in response to thyroid status cannot be ruled out, we conclude that hepatic, renal and cardiac UGT and -glucuronidase activities are not regulated reciprocally with thyroid status.

A physiological role for glucuronidated thyroid hormones: Preferential uptake by H9c2(2-1) myotubes

“…Extrapolating from the observations that H9c2(2-1) cells preferentially take up thyroid hormone glucuronides, and that these stimulate the myoblast differentiation, it can be hypothesized that cardiac muscle cells are targets for a paracrine action of cardiofibroblasts mediated by glucuronidated metabolites of thyroid hormones. We measured considerable ␤-glucuronidase activities in adult-rat whole-heart homogenates (van der Heide et al, 2004) and H9c2(2-1) myotubes (this study), and this indicates that cardiomyocytes can regenerate thyroid hormones by deconjugation of the glucuronidated conjugates. Moreover, adult rat cardiomyocytes and H9c2(2-1) cells contain an iodothyronine deiodinase type 1 activity (van der Heide et al, 2004;van der Putten et al, 2002;Yonemoto et al, 1999), and cardiomyocytes from rat and pig a deiodinase type 2 activity as well (van der Heide et al, 2004;Wassen et al, 2004).…”

“…We measured considerable ␤-glucuronidase activities in adult-rat whole-heart homogenates (van der Heide et al, 2004) and H9c2(2-1) myotubes (this study), and this indicates that cardiomyocytes can regenerate thyroid hormones by deconjugation of the glucuronidated conjugates. Moreover, adult rat cardiomyocytes and H9c2(2-1) cells contain an iodothyronine deiodinase type 1 activity (van der Heide et al, 2004;van der Putten et al, 2002;Yonemoto et al, 1999), and cardiomyocytes from rat and pig a deiodinase type 2 activity as well (van der Heide et al, 2004;Wassen et al, 2004). Most probably, the stimulatory effect on myoblast differentiation upon exposure to thyroid hormone glucuronides are ultimately caused by T3.…”

“…We estimate halftime values that are roughly similar, i.e. 15-55 min, from the time courses of the cellular uptake of T3 by neonatal cardiomyocytes that were incubated in the presence of approximately 100 pM to 10 M T3 (van der Putten et al, 2001;Verhoeven et al, 2002). The capacities for the uptake of thyroid hormones in rat cardiofibroblasts and cardiomyocytes are thus well comparable.…”

“…Cardiofibroblasts are the most abundant cell type in the heart (Agocha and Eghbali-Webb, 1997;Nair et al, 1968), and have the capacity to metabolize thyroid hormones and secrete their metabolites (van der Heide et al, 2002(van der Heide et al, , 2004. This would confer to cardiofibroblasts a role, by endocrine or paracrine interactions, in cardiac physiology.…”

Is the Vascular System a Main Target for Thyroid Hormones? From Molecular and Biochemical Findings to Clinical Perspectives

“…D2 is also a thiol dependent selenoprotein, however, it specifically acts on the outer ring of T4 and is relatively PTU insensitive [24][25][26]. Furthermore, a recent study showed that in the rat heart, D1 specific activity is increased fourfold and cardiac activity was detectable but not sensitive to thyroid status [27]. However, to our knowledge, only a few limited studies have been carried out to clarify the relative contribution of different tissues in the global deiodinative process.…”