Differential regulation by triiodothyronine of substrate-specific uridinediphosphoglucuronate glucuronosyl transferases in rat liver

doi:10.1016/0304-4165(83)90362-8

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 761, Issue 1, 22 November 1983, Pages 58-65

https://doi.org/10.1016/0304-4165(83)90362-8 Get rights and content

Abstract

Hepatic uridinediphosphoglucroonate glucuronosyl transferase (UDPglucuronyltransferase, EC 2.4.1.17) functionally heterogeneus; 4-nitrophenol and bilirubin are representative subtrates for two separated from of the enzyme. UDPglucuronyltransferase activity for bilirubin and 4-nitrophenol was separated from solubilized rat liver microsomes by DEAE-cellulose chromatography and corresponding enzymes were purified. A radioimmunoassay was developed using a rabbit antiserum against purified rat 4-nitrophenol-specific UDPglucuronyltransferase, which precipitated enzyme activities toward both 4-nitrophenol and bilirubin. After treatment with triiodothyronine(T₃) (0.55 mg/kg body weight), hepatic microsomal UDPglucuronyltransferase activity for 4-nitropheelos was increased 400% as compared to controls; the enzyme activity for bilirubin was decreased by 80%; the changes in the substrate-specific enzyme activities were reflected in the enzymatically active fractions separated after DEAE-cellulose chromatography. The changes in enzyme activities paralleled changes in the concentrations of the two corresponing UDP glucuronyltransferase proteins in the chromatographic fractions, as measured by radioimmunoassay. The results indicate that the opposite effects of T₃ on the two forms of UDPglucuronyltransferase activity is due to its differential effect on corresponding enzyme proteins.

References (27)

G.J. Dutton
E. Halac et al.
Biochim. Biophys. Acta
(1967)
P.J. Weatherill et al.
FEBS Lett.
(1978)
N. Malik et al.
J. Biol. Chem.
(1981)
P.L.M. Jansen et al.
J. Biol. Chem.
(1977)
O. Lowry et al.
J. Biol. Chem.
(1951)
M. Bradford
Anal. Biochem.
(1976)
D.J. Fry et al.
Biochem. Soc. Trans.
(1976)
J.P. Gorski
Ph.D. Thesis
(1975)
J.W. Bridges et al.
Biochem. J.
(1965)

H.P.A. Illing et al.

Biochem. J.

(1970)

J.W. Faigle et al.

J. Int. Med. Res.

(1977)

G.J. Wishart

Biochem. J.

(1978)

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^∗: Present address: Department of Pediatrics, University of Chicago, Chicago, IL, 60637, U.S.A.

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Differential regulation by triiodothyronine of substrate-specific uridinediphosphoglucuronate glucuronosyl transferases in rat liver

Abstract

Biochim. Biophys. Acta

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Anal. Biochem.

Biochem. Soc. Trans.

Ph.D. Thesis

Biochem. J.

Biochem. J.

J. Int. Med. Res.

Biochem. J.