George G. Thompson

PREGNANCY AND THE ACUTE PORPHYRIAS

An analysis is presented of the obstetric histories of 50 women with acute porphyria, comprising 39 with acute intermittent porphyria, 3 with variegate porphyria and 8 with hereditary coproporphyria. Fifty‐four per cent of the women with acute intermittent porphyria had an acute attack of porphyria in pregnancy and/or the puerperium. Only one maternal death was recorded. One patient with variegate porphyria and two with hereditary coproporphyria had an attack related to pregnancy. The total fetal wastage was 13 per cent. The babies born to mothers with acute intermittent porphyria, who experienced an acute attack during pregnancy, were smaller than those in which no such attack occurred (P<0·001). In 13 non‐porphyric primigravidae there was a rise in urinary excretion of 8‐aminolaevulinic acid, porphobilinogen and coproporphyrin up to the 28th week of gestation. It is probable that pregnancy has some deleterious effects in acute porphyria but the prognosis of the porphyric pregnancy is much better than the literature suggests.

Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats.

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P‐450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P‐450 than b5. 2 The activity of the rate‐limiting enzyme of haem biosynthesis, δ‐aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P‐450 content. 3 The activity of the haem biosynthetic enzymes δ‐aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.

The biosynthesis of haem in congenital (erythropoietic) porphyria.

Abstract 1. 1. The enzymes of haem biosynthesis have been measured in peripheral blood in two patients aged 6 and 20 yr with congenital (erythropoietic) porphyria. 2. 2. Excessive activity of leucocyte δ-aminolaevulinic acid synthase was found in both patients. 3. 3. The activity of erythrocyte porphobilinogen deaminase was elevated and coupled with a lowered activity of uroporphyrinogen cosynthase, which resulted in excessive production of Series l isomer porphyrin. 4. 4. This was confirmed by isomer analysis of urine which showed an excess in both of coproporphyrin 1. 5. 5. Faecal porphyrin analysis demonstrated excessive quantities of ‘X’ porphyrin in one patient in common with other photosensitizing porphyrias. 6. 6. These results confirm that the primary control of haem biosynthesis in congenital porphyria is at the level of δ-aminolaevulinic acid synthase. with a secondary control point at the level of porphobilinogen deaminase.

Seasonal variation in (δ minolaevulinate synthase and porphyrin content in the harderan gland of the female golden hamster (mesocricetus auratus)

Abstract 1. 1. The activity of δ-aminolaevulinate synthase and porphyrin content of the Harderian gland of the female golden hamster have been measured over one year. 2. 2. A marked seasonal fluctuation in enzyme activity and gland porphyrin content was observed with maxima in both during the summer. 3. 3. These changes have been linked with seasonal increases in temperature and overall lighting, but may also be in part due to humoral factors.

Hormones and the control of porphyrin biosynthesis and structure in the hamster harderian gland.

The hamster Harderian gland seems to present both an excellent model for the control of porphyrin biosynthesis and an unusually robust example of the interrelationship between structure and function. It has been known for some time that 1) the capacity for manufacturing and storing porphyrins and 2) gland histology and ultrastructure are controlled by androgens. Thus, in intact males as well as in gonadectomised animals of either sex treated with androgens, porphyrin synthesis by the Harderian gland is suppressed and the gland tubules characteristically possess two cell types, the cytoplasm of both containing polytubular complexes. By contrast, the Harderian glands of intact females and castrated males synthesise and store large amounts of protoporphyrin, while their tubules possess only one cell type which lacks polytubular complexes. So overarching is the effect of androgens that they have been described as a “coarse tuning” effect on the gland. By contrast, the role of the ovary is both less dramatic and less well understood. In female hamsters, ovariectomy leads to degenerative changes in Harderian gland tubules and (probably) a release of stored porphyrin; at the same time there is a reduction in enzyme levels and new synthesis. The causative hormone in this “fine tuning” is unclear at present. There is now clear evidence that the Harderian gland is also controlled directly by pituitary hormones. In particular, the use of continuous infusion osmotic minipumps has allowed us to demonstrate not only 1) that the expected rise in porphyrins and feminisation of gland morphology does not occur in castrated males receiving the dopamine agonist bromocriptine, but that 2) the simultaneous administration of prolactin does permit these changes; furthermore, 3) the administration of prolactin alone increases porphyrin synthesis above the levels found in untreated castrates. Similarly, bromocriptine administration to ovariectomised females markedly reduces porphyrin synthesis and masculinises gland structure; again, this is reversed by the simultaneous administration of prolactin. Prolactin must therefore be seen as equipotent with androgens in determining gland structure and activity.

Haem biosynthesis in peripheral blood in erythropoietic protoporphyria

The enzymes of haem biosynthesis have been measured in the peripheral blood of 10 patients with erythropoietic protoporyphria. The activity of leukocyte φ‐aminolaevulinic acid synthase was significantly elevated (P < 0.0001) as was that of erythrocyte porphobilinogen deaminase (P = 0′0023). There was a consistent depression of leukocyte ferrochelatase activity (P < 0.0001). This study provides evidence that this disease is related to a generalized genetically determined deficiency of ferrochelatase activity. Control of the pathway is by end product repression and inhibition of φ–aminolaevulinic acid synthase with possible secondary control mechanism at the level of porphobilinogen deaminase.

The effects of selected monopyrroles on various aspects of heme biosynthesis and degradation in the rat.

Abstract The effects of four monopyrroles on porphyrin biosynthesis and excretion in the rat were studied. All four compounds investigated significantly increased total urinary porphyrin excretion and hepatic porphyrin levels while the effects on fecal excretion were equivocal. Peak porphyrin production elicited by treatment with ethyl 3-acetyl-2,4-dimethylpyrrole-5-carboxylate was found to be dose dependent, as was the time of maximum excretion. The effects of 3-ethyl-5-hydroxy-4,5-dimethyl-Δ 3 -pyrrolin-2-one, a compound excreted in abnormally high levels in the urine of patients with hepatic porphyria, were studied in greater depth. It was found that this compound caused an increase in the activity of δ-aminolevulinic acid synthase, in vivo , which was associated with a depression of microsomal levels of heme and cytochrome P -450. This depression of heme levels could not be related to increased catabolism or nonenzymic breakdown. It is suggested that the primary effect of this and the other compounds on porphyrin metabolism is a reduction in heme formation by a mechanism at present unclear.