Multiple UDP‐glucuronyltransferases for the glucuronidation of thyroid hormone with preference for 3,3',5'‐triiodothyronine (reverse T₃)

Abstract

We have studied the glucuronidation of the thyroid hormones T4, T, and rT, by liver microsomes of Wistar, Gunn and WAG rats. Gunn rats have a defect in the gene coding for bilirubin and phenol UDP-glucuronyltransferase (UGT) isoenzymes; WAG rats have a genetic defect in androsterone UGT. In normal Wistar rats UGT activity was &fold higher for rT> than for T, or T,. UGT activities for T4 and rT,, but not for T,, were impaired in Gunn rats. Conversely, UGT activity for T,, but not for T, or rT,, was impaired in WAG rats. Thus, in rat liver rT, is glucuronidated much more rapidly than T, and T,. Our results support the view that T, and rT, are glucuronidated by bilirubin and phenol UGTs and T, by androsterone UGT.

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

“…T 3 is purported to be glucuronidated by UGT2B2 (Beetstra et al, 1991;van Raaij et al, 1993;Visser et al, 1993b). This activity is increased by PCN (Hood and Klaassen, 2000); however, no elevation of UGT2B2 mRNA by PCN was demonstrated in this study.…”

“…Impairment in T 4 glucuronidation was observed in the Gunn rat with no effect on T 3 glucuronidation (Visser et al, 1993b). However, T 3 UGT activity in the Wistar LA rat was severely reduced, whereas T 4 activity was unaffected (Beetstra et al, 1991;Visser et al, 1993b). These data suggest that T 3 and T 4 are likely glucuronidated by different UGT enzymes: T 4 by a member or members of the UGT1A subfamily and T 3 by a member of the 2B subfamily, likely UGT2B2.…”

“…Substrate specificity for thyroid hormones triiodothyronine (T 3 ) and thyroxine (T 4 ) has been studied utilizing the Gunn rat, which possesses a mutation resulting in the loss of all UGT1A enzymes, and the Wistar LA rat that specifically lacks UGT2B2, the enzyme responsible for androsterone glucuronidation (Corser et al, 1987;Iyanagi, 1991). Impairment in T 4 glucuronidation was observed in the Gunn rat with no effect on T 3 glucuronidation (Visser et al, 1993b). However, T 3 UGT activity in the Wistar LA rat was severely reduced, whereas T 4 activity was unaffected (Beetstra et al, 1991;Visser et al, 1993b).…”

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

“…Comparable effects on serum thyroid hormone profiles have also been described in patients given DPH, PB, CBZ, and/or oxcarbazepine (Chin and Schussler 1968;Connel et al 1984;Finucane and Griffiths 1976;Hansen et al 1974;Hirfanoglu et al 2007;Liewendahl et al 1985;Tanaka et al 1987;Vainionpää et al 2004). Notably, T 3 was not comparably affected by UGT-inducing agents in these studies, a finding which has been attributed to primary metabolism of T 3 through sulfation and deiodination rather than glucuronidation in humans, in contrast with rats (Benedetti et al 2005;Findlay et al 2000;Visser et al 1993). More significantly, no notable increase in TSH was reported in most of these clinical studies (Apeland et al 2006;Benedetti et al 2005;Isojärvi et al 2001;Verrotti et al 2009).…”

Toxic and biochemical effects of 3,3′,4,4′-tetrachlorobiphenyl (CB-77) and clophen A50 on eider duckling (Somateria mollissima) in a semi-field experiment

“…PCBs have been reported to influence thyroidhormone levels at two levels at least: by interference of hydroxylated metabolites with the T4 transportation system (Brouwer et aL, 1990, Lans et al, 1993 and by induction of T4-glucuronidation, thus enhancing hepatic elimination of thyroid hormone (Barter & Klaassen, 1992;Beetstra et al, 1991;Visser et al, 1993). Arguments that both mechanisms may actually be involved in eiders and other fish-eating birds have been obtained recently.…”