The inherited enzymatic defect in porphyria variegata

Uroporphyrinogen decarboxylase activity was measured in liver and erythrocytes of normal subjects and in patients with porphyria cutanea tarda and their relatives. In patients with porphyria cutanea tarda, hepatic uroporphyrinogen decarboxylase activity was significantly reduced (mean 0.43 U/mg protein; range 0.25-0.99) as compared to normal subjects (mean 1.61 U/mg protein; range 1.27-2.42). Erythrocyte uroporphyrinogen decarboxylase was also decreased in patients with porphyria cutanea tarda. The mean erythrocyte enzymatic activity in male patients was 0.23 U/mg Hb (range 0.16-0.30) and in female patients was 0.17 U/mg Hb (range 0.15-0.18) as compared with mean values in normal subjects of 0.38 U/mg Hb (range 0.33-0.45) in men and 0.26 U/mg Hb (range 0.18-0.36) in women. With the erythrocyte assay, multiple examples of decreased uroporphyrinogen decarboxylase activity were detected in members of three families of patients with porphyria cutanea tarda. In two of these families subclinical porphyria was also recognized. The inheritance pattern was consistant with an autosomal dominant trait. The difference in erythrocyte enzymatic activity between men and women was not explained but could have been due to estrogens. This possibility was supported by the observation that men under therapy with estrogens for carcinoma of the prostate had values in the normal female range. It is proposed that porphyria cutanea tarda results from the combination of an inherited defect in uroporphyrinogen decarboxylase and an acquired factor, usually siderosis associated with alcoholic liver disease.

Fecal protoporphyrin is increased in patients with variegate porphyria, even during clinical remission, suggesting an enzymatic defect in the terminal portion of the heme biosynthetic pathway. We measured the activities of protoporphyrinogen oxidase, which catalyzes the oxidation of protoporphyrinogen to protoporphyrin, and heme synthase, which catalyzes the chelation of iron to protoporphyrins, in cultured skin fibroblasts from five normal controls and five patients with variegate porphyria. Heme synthase activity was shown to be normal in variegate porphyria cells by direct assay in cell sonicates and indirect assay in intact cells. Protoporphyrinogen oxidase activity, however, was reduced to 43 per cent of normal in sonicates of variegate porphyria cells (0.90 +/- 0.13 vs. 2.12 +/- 0.25 nmol of protoporphyrin per milligram of protein per hour [mean +/- S.E.M.] [P less than 0.005]). We conclude that protoporphyrinogen oxidase activity is deficient in variegate porphyria. Fecal protoporphyrin may increase because an excess amount of protoporphyrinogen is excreted into bile and subsequently auto-oxidized to protoporphyrin.

Hepatic conversion of porphobilinogen to porphyrins was less than 50% of control levels in human subjects with the genetic disease, intermittent acute porphyria. This relative block in heme biosynthesis may be relevant to a concomitant 6- to 10-fold elevation in delta-aminolevulinic acid synthetase activity, since this first and rate-controlling enzyme in the biosynthetic pathway is subject to negative feedback regulation by the end product, heme. A micro-radio-chemical assay of delta-aminolevulinic acid synthetase, and some of its applications, are described.