The Metabolism of Dexamethasone in the Rat

The mode of action of the p-chlorophenylalanine in these animals is not clear. pChlorophenylalanine, in vitro, is not an appreciable inhibitor of phenylalanine hydroxylase, and this is apparently so in vivo also as the lowering of phenylalanine hydroxylase activity shows a delayed response to p-chlorophenylalanine treatment. However, the decrease in phenylalanine hydroxylase activity is not caused by the accumulation ofp-chlorophenylalanine or an inhibitory metabolite of this compound because, when livers fromp-chlorophenylalanine-treated rats are stored at -20°C until the enzyme activity has decayed, no inhibition of freshly prepared purified phenylalanine hydroxylase is observed. One possible explanation is that inhibition is due to a metabolite of p-chlorophenyla!anine which is a tightly bound non-competitive inhibitor, excess of which is further metabolized. It is also possible that the decreased activity results from some incorporation of p-chlorophenylalanine into the enzyme protein, so producing an impaired protein, a suggestion already made by Gil et al. (1970). Phenylalanine hydroxylase is an unstable enzyme and may therefore have a high turnover which would render it particularly susceptible to such an event. This may be so as we observed the enzyme in p-chlorophenylalanine-treated livers is apparently less stable to storage than enzyme from untreated livers. If this latter suggestion is correct it creates a problem with our model in that the treated animals have a raised plasmap-chlorophenylalanine as well as a raised phenylalanine, which may have direct effects on protein synthesis. In projected experiments it will be necessary to compare the experimental animals (i.e. p-chlorophenylalanine-treated phenylalanine-loaded) with untreatedcontrol animals and p-chlorophenylalanine-treated control animals.