Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3)

The two major thyroid hormones are thyroxine (T4) and the more biologically active triiodothyronine (T3), both iodinated derivatives of tyrosine. Active and inactive THs are tightly regulated by enzymes called iodothyronine deiodinases (DIO). The activation occurs via outer ring deiodination (ORD), i.e. removing iodine from the outer, phenolic ring of T4 to form T3, while inactivation occurs via inner ring deiodination (IRD), i.e. removing iodine from the inner tyrosol ring of T4 or T3.

Three types of iodothyronine deiodinases (DIO1-3) have been described in vertebrates that activate or inactivate THs and are therefore important mediators of TH action. All deiodinases are integral membrane proteins of the thioredoxin superfamily that contain selenocysteine in their catalytic centre. Type I deiodinase is capable of converting T4 into T3, as well as to convert rT3 to the inactive thyroid hormone 3,3’ T2, through outer ring deiodination. rT3, rather than T4, is the preferred substrate for DIO1. furthermore, DIO1 has a very high Km (µM range, compared to nM range for DIO2) (Darras and Van Herck, 2012). Type II deiodinase (DIO2) is only capable of ORD activity with T4 as a preferred substrate (i.e., activation of T4 tot T3). DIO3 can inner ring deiodinate T4 and T3 to the inactive forms of THs, reverse T3, (rT3) and 3,3’-T2 respectively (Darras and Van Herck, 2012). DIO2 and DIO3 expression customize the timing and intensity of TH signalling in an organ/tissue-specific way (Russo et al 2021).

Since in fish enzyme activity and thyroid hormone levels are rarely measured in the same study, quantitative understanding of this linkage is limited.

Taxonomic: Deiodinases are important for the activation of T4 to T3 across vertebrates. Therefore, this KER is plausibly applicable across vertebrates. There appear to be differences among vertebrate classes relative to the role of the different deiodinase isoforms in regulating thyroid hormone levels. Maia et al. (2005) determined that in a normal physiological situation in humans the contribution of DIO2 to plasma T3 levels is twice that of DIO1. A DIO2 knockout (KO) mouse however showed a very mild gross phenotype with only mild growth retardation in males (Schneider et al., 2001). It seemed that by blocking the negative feedback system, DIO2 KO resulted in increased levels of T4 and TSH and in normal rather than decreased T3 levels compared to WT. Potential differences in the role of the deiodinase isoforms in the negative feedback system and the final consequences for TH levels across vertebrates is currently not entirely clear. These differences make it difficult to exactly evaluate the importance of DIO2 in regulating serum/tissue T3 levels across vertebrates. Mol et al. (1998) concluded that deiodinases in teleosts were more similar to mammalian deiodinases than had been generally accepted, based on the similarities in susceptibility to inhibition and the agreement of the Km values.

Life stage: Deiodinases are important for the activation of T4 to T3 across all life stages.

Sex: The KE is plausibly applicable to both sexes. Thyroid hormones are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of thyroid hormone levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in thyroid hormone levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.