Biochemical studies on haem and porphyrin metabolism

A series of studies has been carried out, examining the effect and mode of action of various compounds on the haem biosynthetic pathway. a) (1) Allyl isopropyl acetamide (AIA) (300 mg/kg) elevated the activity of rat hepatic Saminolaevulic acid (ALA) synthetase activity tenfcld, and also elevated ALA dehydrase activity and porphyrin and porphyrin precursor excretion. (2) Animal sex had no significant effect on hepatic ALA synthetase activity. (3) In the neonatal period of development hepatic ALA synthetase has a significantly higher activity than in the adult rat. (4) Starvation of rats for 24 hours, with water 'ad lib' significantly elevates hepatic ALA synthetase activity. (5) Vitamin E. significantly depresses porphyrin precursor and porphyrin excretion in rats intoxicated with AIA but has no significant effect on enzyme activities. b) (1) Some barbiturates, when given to rabbits, cause a rise in urinary coproporphyrin excretion while others, suspected of provoking acute attacks of porphyria in man, do not. To investigate this anomaly, the levels of hepatic enzymes occurring early in the biosynthetic pathway have been examined in rats treated with barbiturates. c) (2) Of the nine barbiturates tested all significantly raised the hepatic level of ALA synthetase activity in the rat. This elevation was abolished by the antibiotics, cycloheximide and actinomycin D. (3) These barbiturates may be classified into four significantly different groups, which correspond to the groups of the earlier classification based on urinary coproporphyrin excretion. (4) The chemically related compounds, cyanuric acid, glutethimide and pentazocine, also elevated hepatic ALA synthetase activity in the rat. (5) It is suggested that these results show a direct reason for contraindication of any barbiturates, glutethimide and pentazocine in porphyria. (6) The mechanism of this elevation of enzyme activity by these drugs is discussed. (1) The activity of Saminolaevulic acid synthetase is significantly elevated in the liver of rats and the activity of Saminolaevulic acid (ALA) dehydrase is significantly depressed in the blood of man and rats intoxicated with ethanol. (2) This depression of ALA dehydrase activity follows closely on the elevation of blood ethanol and returns to normal 'pari passu' with the ethanol level. (3) In rats intoxicated with ethanol there is a significant depression of ALA dehydrase activity in the liver and kidney. (4) A scheme is proposed whereby an increase in the intracellular redox potential by ethanol increases sulphydryl cofactor concentrations leading to an inhibition of ALA dehydrase activity. d) (1) A series of twenty C18, C19 and C21 steroids have been examined for e) their effects on rat hepatic ALA synthetase activity. (2) The following: Dehydroepiandrosterone, 17 hydroxy-Pregnenolone, Androstenedione, Androstenediol and Etiocholanolone significantly elevated hepatic ALA synthetase activity in rats. (3) Dehydroepiandrosterone and its sulphate were effective in elevating ALA synthetase activity yet the acetate and glucuronide forms were ineffective in raising activity. (4) The antibiotics Actinomycin D and Cycloheximide abolished this DHA elevation of activity at all times during the induction, thus suggesting that this elevation of enzyme activity is due to a de novo synthesis of enzyme protein. A study has been carried out on four patients with hereditary coproporphyria, two patients in attack and two in remission; (1) All of the patients showed typical excessive excretion of urinary and faecal coproporphyrin with elevated excretion of porphyrin precursors in attack. (2) Both patients in attack had elevated blood ALA dehydrase activity and one a highly elevated hepatic ALA synthetase activity. (3) Both patients in attack had elevated urinary excretion of certain 17 oxosteroids. These results and their relevance to the control and pathogenesis of the haem biosynthetic pathway are discussed