Date of Award
Doctor of Philosophy (PhD)
George D. Sweeney
The mechanism leading to porphyria cutanea tarda has been investigated using experimental porphyria caused by chlorinated aromatic hydrocarbons as a model. This lesion closely ressembles porphyria cutanea tarda in man and was useful in determining the biochemical lesion directly responsible for the defect in heme biosynthesis.
Methodology was developed for rapid and accurate measurement of urinary porphyrins by use of derivative spectroscopy. Based upon this technique, an extraction procedure and assay for urinary porphyrinogens was developed.
The above methodology made possible a detailed examination of excreted intermediates in rats during the development of porphyria caused by hexachlorobenzene. It was found that increased excretion of both porphyrinogens and porphyrins occurred, which disproved the theory that porphyria resulted from accelerated oxidation of porphyrinogens. Detailed analysis of urinary and fecal porphyrins supported the hypothesis that decreased activity of uroporphyrinogen Decarboxylase was the direct cause of the porphyria.
Examination of the susceptibility of inbred strains of mice to porphyria caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin established a relationship between inheritance of responsiveness to induction of aryl hydrocarbon hydroxylase and susceptibility to porphyria. This was confirmed using a back-crossed strain which had been phenotyped for aryl hydrocarbon hydroxylase responsiveness. It was found that susceptibility to porphyria was inherited with the gene controlling aryl hydrocarbon hydroxylase responsiveness.
The requirement for non-heme tissue iron in the development of experimental porphyria was examined by depleting mice of stored iron prior to treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. It was found that iron deficiency protected against morphologic liver damage, depression of uroporphyrinogen decarboxylase activity, and skin lesions caused by the dioxin.
It was concluded that the development of porphyria caused by chlorinated aromatic hydrocarbons is attributable to decreased uroporphyrinogen decarboxylase activity which is brought about by a process in the liver which requires both iron and susceptibility to induction of aryl hydrocarbon hydroxylase.
Jones, Kenneth George, "Studies on the Mechanism of Porphyria Cutanea Tarda" (1979). Open Access Dissertations and Theses. Paper 3231.