Male rat hepatic UDP-glucuronosyltransferase activity toward thyroxine. Activation and induction properties--relation with thyroxine plasma disappearance rate.
Detergent-activation of UDP-glucuronosyltransferase (UGT) isoenzyme(s) involved in thyroxine (T4) glucuronidation in control, phenobarbital (PB)- and 3-methylcholanthrene (3-MC)-treated rats showed that between the four tested detergents, i.e. Triton X-100, Brij 58, Lubrol Px and 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid (CHAPS), optimal activation of T4 UGT was displayed by the zwitterion CHAPS. "Native" versus optimal detergent-activated T4 UGT activity determination revealed that the latency of T4 UGT in microsomes from 3-MC-treated rats was decreased while the latency of T4 UGT in microsomes from PB-treated rats was increased compared to control, and suggest that the UGT isoenzyme(s) involved in the hepatic glucuronidation of T4 is (are) different in PB-treated rats than in 3-MC-treated rats. After a 7-day treatment with 20 mg/kg 3-MC, the activity of T4 UGT was increased 5-fold when determined in "native" and 4-fold when determined in optimal detergent-activated microsomes compared to controls. After a 7-day treatment with 75 mg/kg PB, T4 UGT was equivalent to the control when determined in "native", and increased 1.3-fold when determined in optimal detergent-activated microsomes. The results thus extend evidence that both 3-MC and PB induce the synthesis of UGT protein(s) involved in the glucuronidation of T4, 3-MC being a strong and PB a weak inducer. Hyperthyroid and hypothyroid status, achieved respectively by a 7-day treatment with 100 microns/kg T4 or a 7-day treatment with 10 mg/kg of one of the antithyroid drugs propylthiouracile or methymazole, did not modify T4 UGT activity, suggesting that the isoenzyme(s) conjugating T4 in microsomes from control rats is (are) unlikely to be either 4-nitrophenol or bilirubin UGT isoenzymes. After 14 days of treatment with 75 mg/kg PB, the hepatic glucuronidation rate of T4 was not different from the control when enzyme activity was expressed per mg microsomal protein but was significantly increased 1.4-fold when expressed per whole liver. A significant (1.5-fold) increase in the 125I-T4 plasma elimination rate was also observed in PB-treated rats compared to controls. A strong (3.6-fold) increase in the T4 glucuronidation rate was observed in rats treated with 5 mg/kg 3-MC for 14 days while the 125I-T4 plasma elimination rate was equivalent to the controls. These results demonstrate that there is no direct relation between T4 UGT activity (and subsequent biliary secretion of T4-glucuronides) and T4 plasma clearance and suggest an important contribution of the intestinal exchangeable thyroid hormone pool to the maintenance of blood thyroid hormone levels.
de Sandro
V
V
Département de Recherche sur la Sécurité du médicament, Centre de Recherches de Vitry-Alfortville, Rhône-Poulenc Rorer, Vitry sur Seine France.
Catinot
R
R
Kriszt
W
W
Cordier
A
A
Richert
L
L
D000818:Animals; D003902:Detergents; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood* / Q000493:pharmacokinetics; D014284:Triiodothyronine / Q000097:blood
D003902:Detergents; D014284:Triiodothyronine; D008748:Methylcholanthrene; D013972:Thyrotropin; D014453:Glucuronosyltransferase; D013974:Thyroxine; D010634:Phenobarbital