Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Abstract

Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of T4 glucuronidation by UGT enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in TSH. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (eg, Oatps) and efflux (eg, Mrps) transporters, data exist that support transporters as additional targets sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (T3 more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals has contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also requires further study.

Influence of medications on thyroid function in dogs: An update

“…Administration of phenobarbital to humans results in thyroid hormone alterations similar to, but of substantially lesser magnitude than those observed in rats, resulting in a mild decrease 93 or no change 94‐97 in the serum TT4 concentration and unaltered serum TSH 94,96,97 concentration. The results are consistent with similar mechanisms in the 2 species, but the greater effect on rats is likely the consequence of differences in phenobarbital dosage and susceptibility of the rat to thyroid disruption 98 …”

“…The results are consistent with similar mechanisms in the 2 species, but the greater effect on rats is likely the consequence of differences in phenobarbital dosage and susceptibility of the rat to thyroid disruption. 98 Prospective controlled 40,45,46 and uncontrolled [47][48][49][50] studies of phenobarbital administration in dogs generally identify sizeable and clinically relevant effects on thyroid function. Short-term (<1 month) administration of phenobarbital to healthy dogs resulted in no change in serum TT4, fT4, or TSH concentrations.…”

Disruption of the thyroid hormone system and patterns of altered thyroid hormones after gestational chemical exposures in rodents – a systematic review

“…Disruptions of the HPT axis after gestational exposures appear to be linked to inhibition of TH synthesis and can occur even after relatively modest declines of TH serum levels. In a review of mechanisms of drug metabolizing enzyme inducers and TH alterations, Vansell ( 41 ) has drawn attention to another MOA leading to TSH increases. In studies of liver microsomal enzyme system inducers, the most pronounced disruptions of the HPT axis occurred with substances that promoted T3 glucuronidation and transmembrane transporters important in the biliary excretion of TH conjugates, such as Mrp2.…”

Boscalid shows increased thyroxin‐glucuronidation in rat but not in human hepatocytes in vitro

“…In PRH, the increases in T4‐glucuronidation primarily correlated with UGT2B1 mRNA increase, while in PHH, the correlation of the investigated UGT subtypes was primarily with the UGT1A family members UGT1A1, UGT1A3 and UGT1A9. The UGT enzyme subfamily responsible for thyroid hormone glucuronidation remains unconfirmed (Vansell, 2022); however, in the rat, there is some indication that UGT2B‐family members, in particular UGT2B1, could be related to effects on thyroid hormone metabolism (Bomann et al, 2021; Catania et al, 2003; Goetz & Dix, 2009; Lumb et al, 1978; Miyawaki et al, 2012; Parmentier et al, 2022; Plummer et al, 2021; Saghir et al, 2008; Semler et al, 1989; Shelby & Klaassen, 2006), while others report a connection to UGT1A‐family members for rodents (Chen et al, 2003; Emi et al, 2007; Goetz & Dix, 2009; Plummer et al, 2021; Vansell & Klaassen, 2002). In the present study, T4‐glucuronidation in PRH was associated with UGT2B1 mRNA induction, since it was the only isoform which was statistically significantly induced at D3 and D7 by any of the reference compound or boscalid.…”

“…One of the most relevant and well‐accepted species differences (rat versus human) is the configuration of hormone serum binding proteins (albumin, TTR, and TBG), the corresponding binding and transporting the thyroid hormones T3 and T4 in the body, and their different binding capacities (Bartsch et al, 2018; Foster et al, 2021; Richardson et al, 2015). The differences in constitution of the transport proteins (with their different binding affinities to T3 and T4) in adult rats versus humans affect the capability to degrade and excrete unbound thyroid hormones, for example, by T4 glucuronidation (Vansell, 2022), as in the case of boscalid. Thus, conjugation and excretion of thyroid hormones after exposure to a liver enzyme inducer will much more likely, from a qualitative as well as from a quantitative perspective, be enhanced in the rat, as free T4 is more easily available compared with humans.…”