The regulation of phenylalanine hydroxylase in rat tissues in vivo. Substrate- and cortisol-induced elevations in phenylalanine hydroxylase activity

Abstract

Injections of phenylalanine increased a 2.5-fold in 9 h the hepatic phenylalanine hydroxylase activity of 6-day-old or adult rats that had been pretreated (24h earlier) with p-chlorophenylalanine; without such pretreatment, phenylalanine did not raise the enzyme concentration. This difference is paralleled by the much greater extent to which the injected phenylalanine accumulated in livers of the pretreated compared with the normal animals. The hormonal induction of hepatic phenylalanine hydroxylase activity obeyed different rules: an injection of cortisol was without effect on adult livers but caused a threefold rise in phenylalanine hydroxylase activity of immature ones, both without and after pretreatment with p-chlorophenylalanine. In the latter instance, the effects of cortisol, and of phenylalanine were additive. Actinomycin inhibited the cortisol- but not the substrate-induced increase of phenylalanine hydroxylase, whereas puromycin inhibited both. The results indicate that substrate and hormone, two potential positive regulators of the amount of the hepatic (but not the renal) phenylalanine hydroxylase, act independently by two different mechanisms. The negative effector, p-chlorophenylalanine, also appears to interact with the synthetic (or degradative) machinery rather than with the existing phenylalanine hydroxylase molecules: 24h were required in vivo for an 85% decrease to ensue, and no inhibition occurred in vitro when incubating the enzyme with p-chlorophenylalanine or with liver extracts from p-chlorophenylalanine-treated rats.

Novel Reaction Mechanism of GTP Cyclohydrolase I. High-Resolution X-Ray Crystallography of Thermus thermophilus HB8 Enzyme Complexed with a Transition State Analogue, the 8-Oxoguanine Derivative

“…The GTP concentration is 150 µM in rat liver (63). The 8-oxoguanine/guanine ratios in normal cell DNA are 10.5/10 6 in pig liver and 0.8-5.2/10 6 in HeLa cells (64).…”

The regulation of phenylalanine hydroxylase in rat tissues in vivo. The maintenance of high plasma phenylalanine concentrations in suckling rats: a model for phenylketonuria

“…The assay method for hepatic and renal phenylalanine hydroxylase activity was as described by Greengard & DelValle (1976). Previously established methods were used for the assay of tyrosine aminotransferase (EC 2.6.1.5) (Lin et al, 1958), soluble and mitochondrial aspartate aminotransferase (EC 2.6.1.1) (Herzfeld & Greengard, 1971) and the malate dehydrogenase (EC 1.1.1.37) (Ochoa, 1955) activities of liver extracts.…”

The influence of starvation and tryptophan administration on the metabolism of phenylalanine, tyrosine and tryptophan in isolated rat liver cells

“…Phenylalanine hydroxylase [L-phenylalanine, tetrahydropteridine: oxygen oxidoreductase (4hydroxylating), EC 1.14.16.1] has a longer half-life (Baker & Shiman, 1979;Goodwin, 1979), is induced by glucocorticoid hormones (Freedland, 1963;Greengard & Delvalle, 1976;Namboodiri & Ramasarma, 1978) and tryptophan (Freedland et al, 1964). The activity is, however, reported to be decreased by starvation (Freedland et al, 1964;Yuwiler et al, 1969) and by phenylalanine administration (Freedland et al, 1964).…”