Glucuronidation of thyroid hormone in rat liver: effects of in vivo treatment with microsomal enzyme inducers and in vitro assay conditions.
We investigated the effects of in vivo treatment with different microsomal enzyme inducers, including clofibrate (CLOF), hexachlorobenzene (HCB), 3-methylcholanthrene (MC), 3,3',4,4'-tetrachlorobiphenyl (TCB), and 2,3,7,8-tetrachloro-p-dioxin, as well as of in vitro addition of the detergent Brij 56 on the glucuronidation of T4, T3, and rT3 by UDP-glucuronyltransferase (UGT) activities of rat liver microsomes. The results were compared with measurements of UGT activities for bilirubin, p-nitrophenol (PNP), and androsterone. In general, glucuronidation rates were 5-fold or more higher with rT3 than with T4 or T3 as substrate. In liver microsomes from untreated rats, T4 UGT activity was stimulated by Brij 56 to a maximum of about 2-fold at 0.025% detergent. Treatment of Wistar rats for 4 days with CLOF (200 mg/kg BW.day) resulted in significant increases in UGT activities for T4 (to 154%), rT3 (to 155%), and bilirubin (to 194%), in particular if assayed in the presence of 0.025% Brij 56, but had little effect on the UGT activities for T3, PNP, and androsterone. The CLOF-induced increases in T4 and rT3 UGT activities were not observed in Gunn rats, which have a complete lack of bilirubin UGT activity and greatly impaired PNP UGT activity. Treatment of Wistar rats with a single injection of MC (50 mg/kg BW), TCB (50 mg/kg BW), or 2,3,7,8-tetrachloro-p-dioxin (6.25 micrograms/kg BW) resulted, after 4 days, in 6.3- to 7.3-fold increases in T4 UGT activity and 15.1- to 16.7-fold increases in rT3 UGT activity if determined in the absence of Brij 56, whereas T4 UGT activity was only increased by 33-68% when assayed in the presence of Brij 56. T3 glucuronidation was not affected (with Brij 56) or was increased by only 33-68% (without Brij 56) after treatment with these MC-type inducers. PNP UGT activity was induced 3.6- to 4.3-fold, whereas bilirubin and androsterone UGT activities were changed little by these treatments. Similar findings regarding T4, rT3, PNP, and bilirubin UGT activities were obtained after chronic treatment of WAG rats with HCB, another MC-type inducer. However, WAG rats lack androsterone UGT and show low T3 UGT activity, which was increased about 2.3-fold by HCB treatment. On the basis of these and previous findings it is concluded that at least three UGT isoenzymes are involved in the glucuronidation of thyroid hormone.(ABSTRACT TRUNCATED AT 400 WORDS)
Visser
T J
TJ
Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.
Kaptein
E
E
van Toor
H
H
van Raaij
J A
JA
van den Berg
K J
KJ
Joe
C T
CT
van Engelen
J G
JG
Brouwer
A
A
D000818:Animals; D002592:Cetomacrogol / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism; D014285:Triiodothyronine, Reverse / Q000378:metabolism
D005965:Glucuronates; D000072317:Polychlorinated Dibenzodioxins; D013963:Thyroid Hormones; D014284:Triiodothyronine; D008748:Methylcholanthrene; D014285:Triiodothyronine, Reverse; D002592:Cetomacrogol; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D013974:Thyroxine; C028451:3,4,3',4'-tetrachlorobiphenyl