Decreased Uroporphyrinogen Decarboxylase Activity Research Articles

Dependence of the porphyrogenic effect of 2,3,7,8-tetrachlorodibenzo( p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness

Experimental porphyria caused by chlorinated aromatic hydrocarbons is associated with decreased uroporphyrinogen decarboxylase activity and induction of the microsomal mixed function oxygenase systems, especially cytochrome P 1-450 ( P-448). 2,3,7,8-Tetrachlorodibenzo( p)dioxin (TCDD) produces porphyria in mice and is a specific inducer of cytochrome P 1-450 and its associated aryl hydrocarbon hydroxylase (AHH) activity. To test the hypothesis that susceptibility to porphyria depends on responsiveness to induction of P 1-450, the susceptibility to TCDD-induced porphyria was studied in mice which were genetically responsive ( C57BL 6J ) or nonresponsive ( DBA 2J ) to induction of AHH. To compensate for nonspecific strain differences, mice were obtained by backcrossing the progeny from a C57BL 6J × DBA 2J mating with DBA 2J animals to yield the strain D2(B6D2)F 1. These animals were phenotyped for AHH responsiveness by determining the effect of β-naphthoflavone on zoxazolamine paralysis time. It was found that susceptibility to porphyria was inherited together with AHH responsiveness. Increase in urine porphyrin was similar in mice homozygous and heterozygous for AHH responsiveness but depression of uroporphyrinogen decarboxylase activity was intermediate in the heterozygotic group.

An inherited enzymatic defect in porphyria cutanea tarda: decreased uroporphyrinogen decarboxylase activity.

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.

Hexachlorobenzene-induced porphyria in rats—Relationship between porphyrin excretion and induction of drug metabolizing liver enzymes

A great deal of information concerning the effects of hexachlorobenzene on the haem metabolic pathway has been obtained but little is known about the effects of the drug on lipid metabolism. Consequently, the time course of phospholipid metabolism alteration caused by this xenobiotic was evaluated as related to changes in porphyrin metabolism with the aim to understand better the interregulation of both metabolisms. Female Wistar rats were treated with HCB (1 g/kg) over a 1–8 week period. Individual phospholipid content, [32P] incorporation, total lipid content, lipid peroxidation, uroporphyrinogen decarboxylase activity, its inhibitor generation and porphyrin content, were the parameters measured in the liver of treated rats. Phospholipid metabolism—with the exception of sphingomyelin—presents a biphasic behaviour, in both the endogenous contents and de novo synthesis. The turning point between both phases is the time at which levels of porphyrin and conjugated dienes increase, the latter compounds being involved in oxidative processes. On the other hand, sphingomyelin decreases continuously during the 8 weeks of treatment. It was also found that the malondialdehyde content increased during the early stages. The time sequence for haem metabolism parameters showed that the accumulation of porphyrins occurs after the decrease in uroporphyrinogen decarboxylase activity and the enzyme inhibitor formation, which are early events (first and second weeks). Porphyrins could not by themselves exacerbate uroporphyrinogen decarboxylase impairment or inhibitor generation. This study shows that hexachlorobenzene alters simultaneously phospholipid and porphyrin metabolisms from the early stages, and generates an oxidative environment that favours porphyrinogens and lipid oxidation at later stages. So, this oxidative environment links the alterations on both metabolisms.

Decreased uroporphyrinogen decarboxylase activity in ‘experimental symptomatic porphyria’

An experimental porphyria resembling human acquired symptomatic porphyria from the biochemical viewpoint was induced in rats by prior iron overload followed by the feeding of hexachlorobenzene (HCB). The characteristic accumulation of 8- and 7-carboxyl porphyrins in the livers of these animals suggested a possible defect of decarboxylation of uroporphyrinogen. Uroporphyrinogen decarboxylase activity was readily demonstrable in the livers of normal animals but undetectable in the iron-loaded porphyric animals. In view of the biochemical resemblance between this experimental model and the human disease, it is considered probable that a similar defect exists in the livers of patients with symptomatic porphyria.