Regulation of rat liver tryptophan pyrrolase by its cofactor haem: Experiments with haematin and 5-aminolaevulinate and comparison with the substrate and hormonal mechanisms

Abstract

1. The administration of haematin or 5-aminolaevulinate to rats enhances the activity of liver tryptophan pyrrolase; both endogenous and newly formed apoenzymes become strongly haem-saturated. Haem activation does not stabilize tryptophan pyrrolase. 2. Actinomycin D, puromycin or cycloheximide prevent the activation of the enzyme by 5-aminolaevulinate but not that by haematin. The latter is inhibited by haem-destroying porphyrogens. 3. The combined injection of either haematin or 5-aminolaevulinate with cortisol does not produce an additive effect, whereas potentiation is observed when tryptophan is jointly given with either the cofactor or the haem precursor. 4. Further experiments on the substrate (tryptophan) mechanism of pyrrolase regulation are reported, and a comparison between this and the cofactor and hormonal mechanisms is made., 5. It is suggested that the substrate mechanism may also involve increased haem synthesis. 6. The role of tryptophan pyrrolase in the utilization of liver haem, and as a possible model for the exacerbation by drugs of human hepatic porphyrias, is discussed.

Inhibition of Rat Liver Tryptophan Pyrrolase Activity and Elevation of Brain Tryptophan Concentration by Acute Administration of Small Doses of Antidepressants

“…Such a possible weak inhibition in man together with factors such as: (1) the status of liver haem in vivo (because antidepressants inhibit pyrrolase activity by preventing the haem conjugation of the apoenzyme); (2) the ability of antidepressants to lower circulating corticosteroid levels (Samsonova & Lapin, 1973;Badawy & Evans, 1981); (3) the halflife of basal, induced and activated tryptophan pyrrolase (see Badawy & Evans, 1975); (4) the interval(s) between, and duration of pyrrolase inhibition by, administered therapeutic doses of the drugs, can explain the well known time lag between the start of antidepressant medication and the occurrence of a significant therapeutic response.…”

“…Determination ofliver tryptophan pyrrolase activity Tryptophan pyrrolase activity was determined in fresh-liver homogenates (Badawy & Evans, 1975) either in the absence (holoenzyme activity) or in the presence (total enzyme activity) of added (2 AM) haematin. The apoenzyme activity was obtained by difference.…”

Tryptophan metabolism in alcoholism

“…Substrate activation became known shortly after hormonal induction (Greengard & Feigelson, 1961) and its most distinguishing features are the stabilization of the enzyme by its Trp substrate (Schimke et al 1965a,b) and the increased haem saturation of the enzyme (hence the term activation), which occurs both early and during the entire activation time-course (Greengard & Feigelson, 1961;Badawy & Evans, 1975b). This activation led to the identification of the third mechanism of TP regulation, namely cofactor activation.…”

“…This activation led to the identification of the third mechanism of TP regulation, namely cofactor activation. Here, TP activation is not associated with increased synthesis or stabilization of the enzyme, but, like substrate activation, involves increased haem saturation (Badawy & Evans, 1975b). In fact, haem forms a common link between the substrate and cofactor mechanisms.…”

“…In fact, haem forms a common link between the substrate and cofactor mechanisms. Thus, because Trp does not enhance TP synthesis, the ability of translational inhibitors, such as cycloheximide, to block the Trp effect, an inexplicable observation known for some time, was explained (Badawy & Evans, 1975b) on the basis of Trp enhancing haem biosynthesis. Recently, Ren & Correia (2000) reported that haem may be necessary for glucocorticoid-induced TP mRNA transcription and translation, thus involving haem further in TP regulation.…”