UBC Theses and Dissertations
Stimulation of t-aminolevulinic acid metabolism by uroporphyrinogen I in rat liver homogenates Shivji, Ally
Studies were carried out to investigate the events that prevent the excessive accumulation and excretion of 5-aminolevulinic acid and porphobilinogen, in erythropoietic porphyria and porphyria cutanea tarda. The effect of excess uroporphyrinogens I and IIIr coproporphyrinogen III, and the corresponding porphyrins, on the rate of 4-(14-C) 5-aminolevulinic acid metabolism, were studied. Experiments were carried out with mitochondria free rat liver homogenates, prepared from normal and hexachlorobenzene treated rats. The consumption of 5-aminolevulinic acid was followed by measuring its concentration in content of aliquots, removed at various intervals. The rates of porphobilinogen and porphyrin accumulation were also measured to obtain additional information on the nature of interactions, if any, between the enzymes. The pattern of porphyrin synthesis was examined by high performance liquid chromatographic analysis. In comparing the biochemical events taking place in the normal and porphyric rat liver preparations, the latter had an impaired ability to decarboxylate uroporphyrinogen, as well as a higher capacity (approximately five fold) to metabolize 5-aminolevulinic acid. Of the compounds studied, only uroporphyrinogen I had an effect on the pathway. It stimulated the activities of 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthase in the normal as well as porphyric liver preparations. As a result, 5-aminolevulinic acid metabolism and porphyrin synthesis were stimulated. High performance liquid chromatographic analysis of porphyrin samples showed an accelerated growth of uroporphyrin and heptacarboxylic acid porphyrin fractions (relative to other porphyrins), upon addition of uroporphyrinogen I. The pattern of porphyrin synthesis remained unaltered when uroporphyrinogen I was added to preparations of porphyric livers. The results of these experiments, together with other experimental and clinical data, suggest that uroporphyrinogen I, which directly stimulates 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthase in vitro, probably stimulates the pathway in the same way, in erythropoietic porphyria and porphyria cutanea tarda. Hence, increase in the conversion of 5-aminolevulinic acid and porphobilinogen to porphyrinogens, brought about by uroporphyrinogen I, prevents the accumulation of porphyrin precursors in these two conditions.
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