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Biomedical subjects

M O Doss

Publications and source records attributed to M O Doss.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pharmacokinetic studies of hematoporphyrin derivatives on rat hepatocytes. Protoporphyrin dimethyl ester hematoporphyrin ether versus dihematoporphyrin ether-free hematoporphyrin derivative.

Rat liver cells incorporate monomeric as well as dimeric hematoporphyrin derivatives. Time-dependent incubation assays gave evidence that monomeric compounds are more efficiently incorporated compared to protoporphyrin dimethyl ester hematoporphyrin ether. HL60 cells take up dimeric porphyrins in substantially higher quantities than hepatocytes do. These results allow the conclusion that physiological versus tumor cells behave differently with respect to porphyrin uptake: Whereas physiological cells prefer monomeric porphyrins, tumor cells preferentially incorporate dimeric porphyrins.

Animals↗
PubMed1991

Manifestation of acute intermittent porphyria in patients with chronic inflammatory bowel disease.

In a retrospective study covering 411 acute intermittent porphyria patients, four cases of a coincidence with Crohn's disease or ulcerative colitis were found. Their courses of disease confirmed that patients with chronic inflammatory bowel disease have a higher risk for acute porphyria manifestation. Both malnutrition (glycopenic induction) and sulphasalazine (drug-induced exacerbation) are known as triggering factors for acute porphyric states. Furthermore, diagnosis of acute intermittent porphyria tends to be much more difficult in such cases, as the acute phases of abdominal pain are likely to be associated with the enteral disease process. A delay of diagnosis and therapy of acute hepatic porphyria, however, may endanger the patient by pareses, which could be irreversible or even lethal. Therefore, whenever there is suspicion of a coinciding acute porphyria, urinary screening tests for porphyria should immediately be performed and, if a coinciding acute hepatic porphyria is diagnosed, porphyrogenic drugs like sulphasalazine should be avoided in treatment of chronic inflammatory bowel disease.

Acute Disease↗
PubMed1990

[Diagnosis and therapy of hepatic porphyria].

The term porphyria includes a heterogeneous group of metabolic diseases, which are genetically determined and usually require a "gene-environment interaction" for clinical manifestation of the genetic disposition. Molecular cause for a porphyria is a defective enzyme in the chain of heme biosynthesis. Generally, one differentiates between erythropoietic and hepatic porphyrias. From the clinical point of view, a classification into potentially acute and non-acute forms is of value. Abdominal-neurologic-cardiovascular symptoms dominate the syndromes of intermittently occurring acute hepatic porphyrias, while cutaneous symptoms are related to non-acute, chronic hepatic porphyrias. A combination of the symptoms may occur in porphyria variegata and hereditary coproporphyria. Courses with hepatobiliary involvement are not seldom found in protoporphyria. Only in genuine porphyrias the clinical symptoms can be explained by the pathophysiological consequences of a disturbance in porphyrin metabolism, not, however, in cases of the common secondary porphyrinopathia. The latter porphyrinuria, in contrast to hepatic porphyrias, must be seen as metabolic symptom of another basic disease. Secondary hepatic coproporphyria by itself has no independent and clinical qualities of a disease. The differentiation of hepatic porphyrias into their different classes and enzymologic types, their recognition during latent phases and, especially, their distinction from secondary coproporphyrinurias requires a complex pathobiochemical evaluation with integration of anamnesis and clinical findings.

Humans↗
PubMed1989

[Erythrohepatic protoporphyria with rapidly progressing liver cirrhosis].

A 49-year-old man, known to have had an increased light sensitivity since childhood, was admitted to hospital because of jaundice. Biochemical and morphological examination revealed cirrhosis of the liver with cholestasis. There was a 70-fold increase of protoporphyrin content in the erythrocytes, increased fecal protoporphyrin excretion as well as secondary coproporphyrinuria. Despite symptomatic treatment with ursodeoxycholic acid and cholestyramine hepatic failure ensued for which orthotopic liver transplantation was performed five months after the diagnosis had been made. The patient died two months later of treatment-resistant septicaemia and multiorgan failure. This case demonstrates the need for annual monitoring of liver functions and porphyrin parameters to ensure earliest possible diagnosis of hepatic involvement in erythrohepatic protoporphyria.

Cholestyramine Resin↗
PubMed1989

Relevance of urinary coproporphyrin isomers in hereditary hyperbilirubinemias.

Porphyrin metabolism is impaired in Dubin-Johnson syndrome (DJS), Rotor's syndrome (RS), and Gilbert's syndrome (GS). Urinary coproporphyrin (CP) isomer I is increased in these hereditary hyperbilirubinemias to different degrees: in DJS to 85%, in RS to 70%, and in GS to 50% in the homozygous state (p less than 0.001 compared to controls with isomer I of 27%). Intermediate isomer proportions were found in heterozygote carriers of DJS. An overlapping distribution of the isomer I/III ratio is observed in DJS and RS carriers, homozygous subjects with GS, and individuals suffering from alcohol-related intrahepatic cholestasis. The diagnosis of DJS and RS can be based mainly on porphyrin analysis, but the detection of carriers (heterozygotes) requires additional criteria to distinguish them from patients with intrahepatic cholestasis of a different etiology.

Chromatography, Thin Layer↗
PubMed1989

Hepatobiliary implications and complications in protoporphyria, a 20-year study.

Clinical and biochemical findings in 55 patients with protoporphyria are presented in a 20-year study. The patients revealed a history of photosensitivity, but in 6 cases the diagnosis was not established until a liver abnormality appeared. Protoporphyrin was elevated in erythrocytes and plasma, and also in the feces of most patients. Signs of impaired liver function were observed in 19 patients (35%), also males predominated in this group 72%. Seven subjects (13%) suffered from liver cirrhosis. A female, aged 20, and a male, aged 22, died from fatal liver disease. Erythrocyte protoporphyrin levels in protoporphyria patients with liver complications were 38 +/- 8 mumols/L (mean +/- SEM) compared to 13 +/- 2 (p less than 0.001) for those patients without obvious liver involvement. Patients with hepatobiliary involvement exhibited a pathologic coproporphyrinuria (419 +/- 21 nmol/24h; mean +/- SEM) with an increase in the proportion of isomer I ranging between 43 and 91% of the total (normal value below 31%). Protoporphyrin accumulated in hepatic tissues to various degrees depending on the stage of the disease. Our observations suggest that (a) pathologic coproporphyrinuria with an increase in isomer I serves as a sensitive parameter for recognizing subclinical and clinical hepatobiliary disease, (b) liver involvement may occur more frequently than has previously been reported, and (c) that treatment with cholic acids results in biochemical and clinical improvement. The pathogenetic course from the erythropoietic disease to include hepatic involvement develops in phases. Protoporphyria should be designated as erythrohepatic.

Adult↗
PubMed1989

New form of dual porphyria: coexistent acute intermittent porphyria and porphyria cutanea tarda.

A previously unrecognized form of dual porphyria has been identified in four patients. One male and one female with acute symptoms were diagnosed as having acute intermittent porphyria (AIP), and two males with cutaneous and acute symptoms were diagnosed as having porphyria cutanea tarda (PCT). Biochemically, the excretion of haem precursors showed a complex constellation, with signs characteristic of both AIP and PCT. In one male, a clinical course with both overt PCT and acute manifestations of AIP was observed. Enzyme studies of haem biosynthesis in erythrocytes revealed a dual deficiency, with decreased activity of both porphobilinogen deaminase, as seen in AIP, and uroporphyrinogen decarboxylase, as seen in PCT. A family study showed that the two disorders do not consistently segregate together. These findings suggest that the dual porphyria reflects a double heterozygous condition of coexistent AIP and PCT genes in the same subject.

Adult↗
PubMed1989

Dual porphyria in double heterozygotes with porphobilinogen deaminase and uroporphyrinogen decarboxylase deficiencies.

A coexistent dual deficiency of porphobilinogen deaminase (PBG-D; EC 4.3.1.8) and uroporphyrinogen decarboxylase (EC 4.1.1.37) in erythrocytes was recognized in five individuals, four males and one female. Clinically, the female and one male were diagnosed as suffering from acute intermittent porphyria (AIP), and the other two males were diagnosed as having porphyria cutanea tarda (PCT). Biochemically, the excretion pattern of urinary and fecal heme precursors exhibited a complex constellation with signs characteristic for both AIP and PCT. A coexistent dual enzyme deficiency of PBG-D and URO-D could be confirmed by repeated studies over 10 years. Clinical courses of both disease manifestations were observed. Family investigations have shown that the two disorders do not consistently segregate together. The findings suggest that the dual porphyria reflects a double heterozygous condition of coexistent AIP and PCT genes in the same individual.

Aged↗
PubMed1989

Pharmacokinetic and -dynamic investigations on HL60 cells with a new protoporphyrin dimethyl ester hematoporphyrin dimer.

Pharmacokinetic and -dynamic studies using a novel porphyrin dimer were performed in human line HL60 promyelocytic leukemia cells. Uptake of the dimer into leukemic cells was observed to occur at substantially lower concentrations in comparison to a previously described monomeric dihematoporphyrin ether-free hematoporphyrin derivative. Both dimer and monomer derivatives could be demonstrated to inhibit cell growth, with no remarkable quantitative differences being found in cell proliferation studies regarding [3H]-thymidine incorporation and assay for colony formation. Structurally, the new compound represents an unsymmetrically substituted diethyl ether having protoporphyrin dimethyl ester and hematoporphyrin as substituents. For this reason the compound was designated as protoporphyrin dimethyl ester hematoporphyrin ether.

Chemical Phenomena↗
PubMed1988

[Porphyria cutanea tarda (chronic hepatic porphyria): new aspects on pathogenesis, diagnosis and therapy with a review of the workshop, "Cutaneous porphyrias" at the 17th World Congress of Dermatology in Berlin 1987].

Porphyria cutanea tarda (PCT) is the most frequent type of porphyria. As a rule, it is associated with chronic liver disease. The disturbance of the hepatic porphyrin metabolism is regarded as the cause and center of the disease. Thus PCT is also designated as chronic hepatic porphyria. Reduced activity of hepatic uroporphyrinogen decarboxylase is considered the most important prerequisite for the development of PCT. The cutaneous manifestations are preceded by non-cutaneous latent phases of various degrees. These phases may be proved by urinary porphyrin studies, especially by the increase of uro- and heptacarboxyporphyrins. The hereditary form of PCT can be identified by the determination of the uroporphyrinogen decarboxylase in erythrocytes. The enzyme deficiency in red blood cells follows dominant autosomal inheritance. Alcohol and estrogens are the predominant factors of clinical manifestation. The application of chloroquine in low doses has proved an effective treatment. The present review includes a report on the workshop "Cutaneous Porphyrias", which reflects the clinical, toxic, pharmacogenetic, pathophysiological, enzymologic, and molecular aspects from the authors' point of view.

Chloroquine↗
PubMed1988

On the preparation of dihematoporphyrin ether-free hematoporphyrin derivative.

A dihematoporphyrin ether-free hematoporphyrin derivative has been prepared by a base-catalysed dehydration of hematoporphyrin with sodium hydroxide. The identification was performed by HPLC and mass spectroscopy (FD-MS). The reaction of hematoporphyrin with 1 M sodium hydroxide for 24 h yields more than 90% of the monomeric porphyrins.

Antineoplastic Agents↗
PubMed1987

Porphyrinurias and occupational disease.

Pathologic porphyrinuria in man is based on a complex etiology and pathogenesis. In hepatic porphyrias, coproporphyrinuria is usually only one of the pathognomostic porphyrin parameters in the urine. Secondary coproporphyrinuria means that an increased excretion of coproporphyrin occurs as the biochemically dominant symptom of a disturbance in porphyrin and heme metabolism during an intoxication, individual condition, or basic disease. Certain foreign and environmental chemicals, such as hexachlorobenzene, polyhalogenated aromatic hydrocarbons, vinyl chloride, and dioxin, alter the heme pathway functionally. Increased porphyrinuria can follow as a toxic response that is differentiated into secondary coproporphyrinuria and chronic hepatic porphyria. This is characterized by a simultaneous increase in hepatic and urinary uroporphyrin and heptacarboxylic porphyrins, owing to inhibition of hepatic uroporphyrinogen decarboxylase. Most of the coproporphyrinurias observed in man are caused by alcohol ingestion. Dioxin, vinyl chloride, and polyhalogenated biphenyls induce an incipient subclinical stage of chronic hepatic porphyria in persons with normal red cell uroporphyrinogen decarboxylase. In contrast, exposure to dioxin on the part of persons with inherited uroporphyrinogen decarboxylase deficiency can cause latent chronic hepatic porphyria to develop into PCT. Coproporphyrinuria and latent chronic hepatic porphyria do not produce clinical symptoms. Secondary porphyrinuria with transition to chronic hepatic porphyria is a metabolic response following various toxic and pathologic conditions; it serves as a sensitive index for chemical exposure and occupational disease.

Alcoholic Intoxication↗
PubMed1971

Tests for porphyria.

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Chromatography, Ion Exchange↗
PubMedDate not supplied

Variegate porphyria with coexistent decrease in porphobilinogen deaminase activity.

Variegate porphyria is a rare disease caused by a deficiency of protoporphyrinogen oxidase. In most cases, the clinical findings are a combination of systemic symptoms similar to those occurring in acute intermittent porphyria and cutaneous lesions indistinguishable from those of porphyria cutanea tarda. We report on a 24-year-old woman with variegate porphyria who, after intake of lynestrenol, developed typical cutaneous lesions but no viscero-neurological symptoms. The diagnosis was based on the characteristic urinary coproporphyrin and faecal protoporphyrin excretion patterns, and the specific peak of plasma fluorescence at 626 nm in spectrofluorometry. Biochemical analysis revealed that most of the family members, though free of clinical symptoms, excrete porphyrin metabolites in urine and stool similar to variegate porphyria, accompanied by a significant decrease of porphobilinogen deaminase activity of a range which is ordinarily found in patients with acute intermittent porphyria only (approximately 50%). These data first led to the assumption of two separate and independently inherited genetic defects, similar to the dual porphyria of Chester. Molecular analysis, however, revealed only a missense mutation of the protoporphyrinogen oxidase gene, but not of the porphobilinogen deaminase gene. Thus, in the family presented, porphobilinogen deaminase deficiency is likely to be a phenomenon secondary to the genetic defect of protoporphyrinogen oxidase.

Adult↗
PubMedDate not supplied

Alcohol and porphyrin metabolism.

Alcohol is a porphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive consumption of alcohol, a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria is observable, which can become persistent in cases of alcohol-induced liver damage. Nowadays, the alcohol-liver-porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are considered to be molecular regulatory diseases, in contrast to non-acute, chronic hepatic porphyria, clinically appearing as porphyria cutanea tarda (PCT). Porphyrins do not accumulate in the liver in acute porphyrias, whereas in chronic hepatic porphyrias they do. Thus, chronic hepatic porphyria is a porphyrin-accumulation disease, whereas acute hepatic porphyrias are haem-pathway-dysregulation diseases, characterized in general by induction of delta-aminolevulinic acid synthase in the liver and excessive stimulation of the pathway without storage of porphyrins in the liver. The clinical expression of acute hepatic porphyrias can be triggered by alcohol, because alcohol augments the inducibility of delta-aminolevulinic acid synthase. In chronic hepatic porphyrias, however, which are already associated with liver damage, alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Especially in persons with a genetic deficiency of uroporphyrinogen decarboxylase, but also in patients with the so-called sporadic variety of PCT, alcohol is able to transform an asymptomatic coproporphyrinuria into PCT. Alcohol has many biochemical and clinical effects on porphyrin and haem synthesis both in humans and laboratory animals. Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase. Therefore, teetotalism is a therapeutically and prophylactically important measure in all types of hepatic porphyrias.

Acute Disease↗