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Biomedical subjects

M Doss

Publications and source records attributed to M Doss.

At least 37 records · Page 2Linked to original sources
PubMed1985

Hereditary hepatic porphyria with delta aminolevulinate dehydrase deficiency: immunologic characterization of the non-catalytic enzyme.

Immunoreactive delta-aminolevulinate dehydrase (ALA-D) was measured in lysates from two porphyric patients with ALA-D deficiency (enzyme activities were below 2% of the normal level). By using two different immunologic methods, we found a cross-reactive immunologic material (CRIM+) which corresponded to 20% and 33% of the control level. Therefore the molecular basis that accounts for the deficiency of ALA-D in these patients is a structurally modified enzyme. The methods used to determine the molecular weight (by Western blotting) and the isoelectric point (by chromatofocusing) of the mutants did not show any difference by comparison with the normal enzyme.

Electrophoresis, Polyacrylamide Gel↗
PubMed1985

Hereditary uroporphyrinogen-decarboxylase deficiency predisposing porphyria cutanea tarda (chronic hepatic porphyria) in females after oral contraceptive medication.

Porphyria cutanea tarda (PCT) was diagnosed in 27 women aged 23-48 years (mean, 35 years) who had been under oral-hormonal-contraceptive medication for 1-18 years, in 3 women under substitutional estrogen treatment in the menopause, and in 2 men aged 65 and 76 years after estrogen treatment of prostatic carcinoma. In all patients, total urinary porphyrin excretion was elevated, with an average uro- and heptacarboxyporphyrin predominance of 88%, thus proving PCT. Of the patients, 84% showed a significant decrease of erythrocyte uroporphyrinogen-decarboxylase (UD; EC 4.1.1.37) activity to approximately 50% of control levels suggesting a hereditary predisposition for the development of a chronic hepatic porphyria. Estrogens and alcohol are capable of reducing hepatic UD activity. Women with hereditary red cell UD deficiency may be regarded as predisposed to PCT when under estrogen intake, especially in combination with the potentiating influence of alcohol and chronic liver disease. Normal erythrocyte UD values in patients with additive alcohol consumption may implicate a stronger inhibitory effect for alcohol on UD, suggesting a merely toxic form of chronic hepatic porphyria.

Adult↗
PubMed1985

Clinical and experimental investigations of vasopressin secretion in acute porphyrias.

In 41 patients suffering from acute hepatic porphyrias the arginin-vasopressin (AVP) levels in their urine were measured by RIA. In 6 patients, AVP secretion was normal; in 8 cases AVP levels were significantly elevated, while 27 cases showed decreased levels of AVP (p less than 0.001). A linear correlation between AVP secretion and urine volume was not found. In animal experiments, 20 rats were treated with delta-aminolevulinic acid (ALA), (1.5 mmol/kg/24 h and 1.5 mmol/kg/48 h) for 4 weeks. Afterwards vasopressin production in the hypothalamo-hypophyseal system was analysed by the immunoperoxidase technique and a microdensitometric method. In ALA-treated animals, AVP positive neurones showed coarse-grained granules of different intensity and a distinct increase of peroxidase positive granules in the zona interna of the eminentia mediana. Furthermore, in comparison with the control group in ALA-treated animals the mean diameter of nuclei in AVP positive neurons was greater. While animals treated daily showed an increase of transmission in the pituitary, microdensitometric findings in animals treated at 48 hourly intervals showed an equal transmission in AVP producing nuclei compared to the control group. Our results seem to point to a toxic effect of porphyrin precursors on the CNS, which may also induce via hypothalamus lesion either diabetes insipidus or a SIADH-syndrome.

Acute Disease↗
PubMed1985

Hyperinsulinemia in acute intermittent porphyria.

Diabetic oral glucose tolerance test together with hyperinsulinemia in a patient with decompensated acute intermittent porphyria is contrasted to normal findings in compensated acute intermittent porphyria (AIP). Results point to the essential role of insulin for the depression of porphyrin precursor overproduction as a mediator of the "glucose effect".

Acute Disease↗
PubMed1985

Acute lead intoxication due to intravenous injection.

A case of acute lead poisoning due to intravenous injection of lead acetate is reported. The patient developed clinical and biochemical symptoms characteristic for acute hepatic porphyrias. Elevated urinary 5-aminolaevulinic acid and low porphobilinogen correlated to a lead-induced inhibition of 5-amino-laevulinic acid dehydrase with diagnostically indicative reactivation rates by zinc and dithiothreitol. Urinary coproporphyrin excretion was also increased. Additional findings included anaemia and toxic hepatitis. Under the influence of elimination therapy with D-penicillamine pathologic parameters normalized. Except for transient neuralgic pains the patient did not experience any neurologic dysfunctions, thus contrasting the findings in chronic lead intoxication.

Adult↗
PubMed1985

"Glucose effect" and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias.

The effect of glucose on drug-promoted induction of porphyrin synthesis was studied in chick embryo liver cell culture with and without the addition of exogenous delta-aminolaevulinic acid (ALA). Induction of ALA synthase was abolished by haemin or glucose. Less than 10% of porphobilinogen is converted into protoporphyrin. Protoporphyrin synthesis cannot be enhanced by high ALA concentrations. The conversion of exogenous ALA into porphyrins decreases with increasing concentrations of ALA from 0.1 to 2.0 mmol/l, whereas porphobilinogen accumulates, thus reflecting the rate limiting function of uroporphyrinogen synthase, which is not influenced by glucose. This needle-eye-like function of uroporphyrinogen synthase within the porphyrin biosynthetic chain explains the urinary increase of ALA and porphobilinogen in the acute phase of variegate and coproporphyria, similar to that in acute intermittent porphyria. The "glucose effect" was also investigated in vivo in humans in 32 courses of hereditary acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria and porphobilinogen synthase defect porphyria). Patients were treated with high carbohydrate intake (approximately 500 g/24 h), mainly in the form of glucose infusions. There was a resulting consistent and highly significant decrease of porphyrin biosynthesis metabolites, accompanied by clinical improvement in most of the patients.

5-Aminolevulinate Synthetase↗
PubMed1984

Lead poisoning as a toxogenetic disease.

In two non-related patients suffering from acute lead intoxication a persistent decrease in red cell delta-aminolevulinic acid dehydratase (synonym: porphobilinogen synthase) activity of 30%-60% of controls was noted after treatment and normalisation of lead levels and heme precursors in urine and blood. An inherited enzyme deficiency was suggested and confirmed by a subnormal activity in the mothers of both patients. These four persons are considered as heterozygotes with an increased sensitivity to lead exposure.

Adult↗
PubMed1984

Vinyl chloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria.

A chronic hepatic disorder of porphyrin metabolism was found in 36 workers with vinyl chloride (VC)-induced hepatic injury following long-time industrial exposure. Pathologic porphyrinuria, especially secondary coproporphyrinuria with transition to subclinical chronic hepatic porphyria, is a consistent pathobiochemical parameter for the recognition of VC hepatic lesions. The porphyrinuria is of diagnostic value for the incipient toxic phase. Erythrocyte uroporphyrinogen decarboxylase activity studied in six cases with initial chronic hepatic porphyria was normal, suggesting that VC affects only this enzyme in the liver.

Chemical Industry↗
PubMed1984

Lead poisoning in inherited delta-aminolevulinic acid dehydratase deficiency.

delta-Aminolevulinic acid dehydratase (ALA-D), respectively porphobilinogen synthase, EC 4.2.1.24) activity can be lowered by toxic, metabolic and hereditary factors. A 30-year-old painter was suffering from lead poisoning with an acute abdominal-neurologic syndrome and anemia. Blood lead was measured at 414 micrograms/l. Urinary ALA and coproporphyrin excretion as well as erythrocyte protoporphyrin had increased extremely, whereas ALA-D activity in erythrocytes had decreased extremely to 8% of controls. Excretion parameters, protoporphyrin, hemoglobin and lead returned to normal after treatment, but four years later ALA-D activity still remained diminished (30% of controls). An inherited enzyme deficiency was assumed and found in the mother, analogous to the subnormal ALA-D activity in heterozygotes of four other families. The inherited enzyme deficiency sensitized the patient to lead exposure and intoxication, which is a toxogenetic disease in this case.

Adult↗
PubMed1984

Development of chronic hepatic porphyria (porphyria cutanea tarda) with inherited uroporphyrinogen decarboxylase deficiency under exposure to dioxin.

Exposure to dioxin triggered a clinically manifest chronic hepatic porphyria (porphyria cutanea tarda) in two patients (brother and sister) with hereditary uroporphyrinogen decarboxylase deficiency. The patients showed a decrease of erythrocyte uroporphyrinogen decarboxylase activity to approximately 50% of controls even in reinvestigations after three years, whereas clinical symptoms and porphyrinuria had improved considerably. Only a subclinical phase of chronic hepatic porphyria persisted. Subnormal uroporphyrinogen decarboxylase activity could be determined in altogether nine family members. The remission of porphyria cutanea tarda into a subclinical phase occurred after chloroquine therapy. Subclinical phases of chronic hepatic porphyria (type A) in other family members remitted without special therapy. Among the 60 persons dioxin-exposed by the Seveso accident, a secondary coproporphyrinuria was found in 22% of examined patients with transition to a subclinical chronic hepatic porphyria in 5 cases. The changes had subsided completely after one year. A persistence of the transition state in 3 cases is probably due to alcohol influence. None of these cases developed a porphyria cutanea tarda. The investigations showed that a hereditary disposition is necessary for biochemical and clinical expression of chronic hepatic porphyria after a unique dioxin exposure. This is not given in the sporadic cases: after a unique dioxin exposure they indeed develop a symptomatic disturbance of porphyrin metabolism but not a clinically relevant chronic hepatic porphyria. We conclude that a unique acute exposure to dioxin can trigger the chronic hepatic porphyria disease process in persons with an underlying genetic abnormality of uroporphyrinogen decarboxylase.

Adult↗