Regulation of Rat Hepatic Phenylalanine Hydroxylating System In Vivo

Abstract

Phenylalanine hydroxylase (PAH) catalyses the first and rate-limiting step in the catabolism of phenylalanine. Tetrahydrobiopterin (BH4) is an essential cofactor (co-substrate) for this reaction. BH4 is regenerated by pterin 4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase. The abundance of hepatic PAH diminishes (to 60% of control values) in rats fed a 40% glycerol diet for 7 days. In this experimental model, there is a close coordination of the affects on the hepatic concentration of BH4, guanosine triphosphate (GTP), PAH activities and cytoplasmic PCD activity. Western Blot analysis confirmed that the diminution in cytoplasmic PCD activity was due to a lower abundance of the latter protein in vivo. GTP cyclohydrolase I activity was not altered. PCD has been identified as a dimerization cofactor (DCoH) for HNFla resulting in higher transcriptional activity of HNF1α. There is evidence to suggest that hepatic PAH is regulated by HNFα. Our data support a role for PCD/DCoH in the regulation of the expression of phenylalanine hydroxylase in the regulation of the expression phenylalanine hydroxylase in rat liver in vivo.