Thyroid hormone suppresses hepatic sterol 12 alpha-hydroxylase (CYP8B1) activity and messenger ribonucleic acid in rat liver: Failure to define knownthyroid hormone response elements in the gene

Sterol 12 alpha-hydroxylase (CYP 8B1) is a microsomal cytochrome P450 enzym e involved in bile acid synthesis that is of critical importance for the co mposition of bile acids formed in the river. Thyroidectomy of rats caused a more than twofold increase of CYP8B1 and an almost fourfold increase of th e corresponding mRNA levels compared to sham-operated rats. Treatment of in tact rats with thyroxine caused a 60% reduction of enzyme activity and a 50 % reduction of mRNA levels compared to rats injected with saline only. To i nvestigate whether the promoter of the gene contains thyroid hormone respon se elements, the complete structure of the rat gene was defined. In similar ity with the corresponding gene in mouse, rabbit and man, the rat gene was found to lack introns. It had an open reading frame containing 1500 bp corr esponding to a protein of 499 amino acid residues. Although thyroid hormone decreased CYP8B1 activity and mRNA in vive, no hitherto described thyroid hormone response elements were identified 1883 bases upstream of the transc ription start site. It is concluded that rat CYP8B1 is regulated by thyroid hormone at the mRNA level. The results are discussed in relation to the st ructure of the gene coding for the enzyme. (C) 1999 Elsevier Science B.V. A ll rights reserved.