Effects of pethoxamid treatment on the disposition of thyroxine in rats

Appavu Chandrasekaran; Karin Bentley; Robert McClanahan; Gopinath Nallani

doi:10.1016/j.taap.2024.116959

Effects of pethoxamid treatment on the disposition of thyroxine in rats

Toxicol Appl Pharmacol. 2024 May 9:487:116959. doi: 10.1016/j.taap.2024.116959. Online ahead of print.

Authors

Appavu Chandrasekaran¹, Karin Bentley¹, Robert McClanahan², Gopinath Nallani³

Affiliations

¹ FMC Corporation, 2929 Walnut St, Philadelphia, PA, USA.
² Frontage Laboratories, 10845 Wellness Way, Concord, OH 44077, USA.
³ FMC Corporation, 2929 Walnut St, Philadelphia, PA, USA. Electronic address: Gopinath.Nallani@fmc.com.

PMID: 38734151
DOI: 10.1016/j.taap.2024.116959

Abstract

Pethoxamid (PXA) is a chloroacetamide herbicide that works by inhibiting the germination of target weeds in crops. PXA is not a genotoxic agent, however, in a two-year chronic toxicity study, incidence of thyroid follicular cell hyperplasia was observed in male rats treated at a high dose. Many non-mutagenic chemicals, including agrochemicals are known to produce thyroid hyperplasia in rodents through a hepatic metabolizing enzyme induction mode of action (MoA). In this study, the effects of oral gavage PXA treatment at 300 mg/kg for 7 days on the disposition of intravenously (iv) administered radio-labeled thyroxine ([¹²⁵I]-T4) was assessed in bile-duct cannulated (BDC) rats. Another group of animals were treated with phenobarbital (PB, 100 mg/kg), a known enzyme inducer, serving as a positive control. The results showed significant increase (p < 0.01) in the mean liver weights in the PB and PXA-treated groups relative to the control group. The serum total T4 radioactivity C_max and AUC₀_-₄ values for PB and PXA-treated groups were lower than for the control group, suggesting increased clearance from serum. The mean percentages of administered radioactivity excreted in bile were 7.96 ± 0.38%, 16.13 ± 5.46%, and 11.99 ± 2.80% for the control, PB and PXA groups, respectively, indicating increased clearance via the bile in the treated animals. These data indicate that PXA can perturb the thyroid hormone homeostasis in rats by increasing T4 elimination in bile, possibly through enzyme induction mechanism similar to PB. In contrast to humans, the lack of high affinity thyroid binding globulin (TBG) in rats perhaps results in enhanced metabolism of T4 by uridine diphosphate glucuronosyl transferase (UGT). Since this liver enzyme induction MoA for thyroid hyperplasia by PB is known to be rodent specific, PXA effects on thyroid can also be considered not relevant to humans. The data from this study also suggest that incorporating a BDC rat model to determine thyroid hormone disposition using [¹²⁵I]-T4 is valuable in a thyroid mode of action analysis.

Keywords: Biliary Excretion; Pethoxamid; Phenobarbital; T4-Glucuronidation; Thyroxine.