The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3)

Abstract

1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0 μM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

“…Thus, the characterization of CBD pharmacokinetics in our cohort expands the information on children with refractory epilepsy for future meta‐analysis and comparative studies. CBD, like most highly lipophilic drugs, exhibits an irregular and partial absorption from the gastrointestinal tract 13 and undergoes metabolism via the cytochrome P450 enzymes and UDP‐glucuronosyltransferase 14,15 . Therefore, it is plausible that the high interpatient variability in CBD exposures of 80%, 85%, and 117% in AUC 0–6 , C max / D , and C0/ D , respectively, could result from differences in the absorption process due to physicochemical properties and variable expression of metabolic enzymes and is probably due to drug‐drug interactions.…”

Endocrine disruptors also function as nervous disruptors and can be renamed endocrine and nervous disruptors (ENDs)

“… 161 PCB methyl sulfones PCB metabolite Kato et al [ 397 ]: reduction of thyroid hormone levels by different mechanisms. 162 Tetraiodothyronine Natural hormone * Chen et al [ 398 ]: inhibition of UDP-glucuronosyltransferases. Dos Reis-Lunardelli et al [ 399 ]: can alter animal behavior and learning and memory in rats.…”

Real-World Evidence of Factors Affecting Cannabidiol Exposure in Children with Drug-Resistant Developmental and Epileptic Encephalopathies

“…Experimental results from in vitro and animal studies strongly suggest that thyroid hormones reduce CYP3A activity in humans, affecting the main pathway for CBD metabolization [ 42 ]. Also, levothyroxine-mediated UGT inhibition has been described [ 43 ]. Both findings in the present study and our previous report are the only evidence of the influence of levothyroxine on CBD exposure.…”