Diminished hepatic triiodothyronine production in Gunn rats.
The liver is a major site of conversion of thyroxine (T4) to the more active thyroid hormone 3,5,3'-triiodothyronine (T3). Hepatic T4 to T3 conversion is altered by a variety of pathological processes and pharmacological agents. We studied T4 to T3 conversion in glucuronyl transferase deficient homozygous Gunn rats because they have a hepatic enzyme abnormality which leads to hyperbilirubinaemia, and also because they have been reported to have alterations in thyroid hormone metabolism. An in vitro incubation system employing the 10,000 X g supernatant of liver homogenate was used, and T3 production was measured by radioimmunoassay. Experiments were done using substrate concentrations ranging from 0.56 to 20 microM, tissue protein in concentrations ranging from 0.625 to 20 mg and incubation times of 15 to 60 min. T3 production by liver homogenates from homozygous Gunn rats in these studies ranged from 29 to 70% of that produced by liver homogenates from phenotypically normal heterozygous Gunn rats. The deficit in hepatic T3 production by homozygous rats could not be overcome by increasing cofactor concentrations. After ultracentrifugation at 100,000 X g, T4-5'-deiodinase activity was found primarily in the 100,000 X g sediment fraction. Homozygous rat liver 100,000 X g sediment T3 production was 55% of that of the heterozygous rat liver 100,000 X g sediment. Liver cytosol from both homozygous and heterozygous rats inhibited microsomal T4-5'-deiodinase activity similarly. Addition of unconjugated bilirubin to liver homogenates resulted in reduction of T3 production in livers from both homozygous and heterozygous rats.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D008099:Liver / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011911:Rats, Gunn; D013347:Subcellular Fractions / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000096:biosynthesis*
D011506:Proteins; D014284:Triiodothyronine; D013974:Thyroxine; D001663:Bilirubin