Porphyria In Rats Research Articles

A reciprocal relationship between the induction of δ-aminolevulinic acid synthetase and drug metabolism produced by m-dichlorobenzene

The daily administration of large doses of m-dichlorobenzene (m-DCB) causes experimental hepatic porphyria in rats by induction of δ-aminolevulinic acid synthetase (ALA synthetase). However, smaller doses of m-DCB produce a biphasic stimulation of both urinary coproporphyrin excretion and liver ALA synthetase. The decline of ALA synthetase and urinary coproporphyrin despite continued daily dosage is associated with an increase in activity of the liver drug-metabolizing systems and decreasing serum m-DCB levels. The most probable explanation for the self-limiting action of m-DCB is stimulation by the drug of its own metabolism.

The in vivo effect of vitamin E in experimental porphyria

The induction of experimental porphyria in rats by allylisopropylacetamide is characterized by elevation of hepatic δ-aminolevulinate synthetase and dehydratase activities. The administration of vitamin E 6 h prior to initiation of the porphyrinogenic regimen prevented porphyria through a control exercised on the activities of the two hepatic enzymes. The bone marrow of porphyric animals showed enhanced synthetase activity which was prevented by vitamin E. In this paper, evidence is presented to show that vitamin E deficiency increases susceptibility to the induction of δ-aminolevulinate synthetase by allylisopropylacetamide, indicating that the vitamin is in some way involved in the regulation of the inducible enzyme. Since other studies have shown that the normal constitutive enzyme is vitamin E dependent in vivo, the question is posed whether the normal and inducible forms represent isozymes of δ-aminolevulinate synthetase.

Some Observations on Hexachlorobenzene Induced Experimental Porphyria

The occurrence in Turkey of numerous cases of cutaneous porphyria, induced by the fungicide hexachlorobenzene (1, 2), was followed by the demonstration that the same toxin induced porphyria in rats (3, 4). It was anticipated that this disorder in rats would provide a useful model for the study of hepatic porphyria with -associated photosensitivity, the form of the disease presented by the Turkish patients. Although initial attempts failed to demonstrate photosensitivity in rats with hexachlorobenzene-induced porphyria (5, 6), we found that by suitable experimental manipulation it was not only possible to produce gross photosensitivity reactions but also certain other features analogous to those found in photosensitive porphyria of man.

811. Chlorinated benzenes and disturbances in porphyrin metabolism: Rimington, C. & Ziegler, G. (1963). Experimental porphyria in rats induced by chlorinated benzenes. Biochem. Pharmac.12, 1387. Haeger-Aronsen, Birgitta (1964). Experimental disturbance of porphyrin metabolism and of liver catalase activity in guinea pigs and rabbits. Acta pharmac. tox.21, 105.

811. Chlorinated benzenes and disturbances in porphyrin metabolism: Rimington, C. & Ziegler, G. (1963). Experimental porphyria in rats induced by chlorinated benzenes. Biochem. Pharmac.12, 1387. Haeger-Aronsen, Birgitta (1964). Experimental disturbance of porphyrin metabolism and of liver catalase activity in guinea pigs and rabbits. Acta pharmac. tox.21, 105.

Experimental porphyria in rats induced by chlorinated benzenes

Like hexachlorobenzene, the lower chlorinated benzenes are able to induce experimental hepatic porphyria in rats. Feeding of mono-, di-, tri and tetrachloro-benzenes to male albino rats was followed first by increased urinary coproporphyrin excretion, later by rise in porphobilinogen and δ-aminolaevulic acid. There are differences in the excretory pattern between animals treated with lower chlorinated benzenes and Sedormid or allylisopropylacetamide (AIA). Liver GSH content was found to be reduced in starved rats after administration of 1, 2, 4-trichlorobenzene. GSH given to rats, highly porphyric due to 1,2,4-trichlorobenzene-intoxication, had a protective effect. Preliminary investigations were made of hepatic pyridine nucleotide levels in rats made porphyric by intoxication with chlorinated benzenes, AIA or Sedormid. Some deviations from normality were observed. Hair loss was noted due to follicular hyperkeratosis similar to the acneiform eruptions seen in man due to chlorinated compounds. The experimental animals showed no signs of photosensitivity.

Acquired porphyria in man and rat due to hexachlorobenzene intoxication.

SINCE 1956, an outbreak of cutaneous porphyria involving several thousand cases has been noted in three south-eastern provinces of Turkey1. Affected individuals, predominantly children and adolescents, exhibit photosensitivity with hydroa aestivale, marked porphyrinuria and hepatomegaly, but no abdominal or neurological symptoms. Epidemiological studies suggested the possibility that the disease might be related to the ingestion of wheat treated with a fungicide containing hexachlorobenzene1,2. Since direct verification of this possibility by field investigation has not been obtained1, and since the available toxicological information on hexachlorobenzene is conflicting3, an attempt was made to produce hexachlorobenzene porphyria in rats.