Excretion Of Δ-aminolevulinic Acid Research Articles

Acute hepatic porphyria syndrome with porphobilinogen synthase defect

On the basis of metabolite and enzyme studies a new type of acute hepatic porphyria with porphobilinogen synthase defect and repeated intermittent acute manifestations, abdominal colics, tachycardia and hypertension, and a persistent neurological syndrome was found in two young male patients. The main characteristic features are the following: 1. 1. High urinary δ-aminolevulinic acid excretion( ⪢ 1 mmol/24hr), slight increase of porphobilinogen (up to 25 μmol/24 hr) and high increase of porphyrins (up to 22 μmol/24 hr) with coproporphyrin dominance. 2. 2. Normal fecal and liver porphyrins. 3. 3. Slight increase of erythrocyte protoporphyrin. 4. 4. Decrease of porphobilinogen synthase activity in erythrocytes in both cases below 1% of healthy and not lead-exposed persons; normal activities of uroporphyrinogen synthase and decarboxylase in erythrocytes. 5. 5. Low-normal lead concentrations in blood and low-normal lead excretion in urine in both cases; normal lead content in bone. 6. 6. Normal plasma and urinary amino acids. 7. 7. Irrelevant hepatological (liver biopsy), general clinical chemical and hematological findings. 8. 8. Diminished activity of porphobilinogen synthase in nearly all family members of both patients. From these investigations it can be concluded that there is no exogeneous, “toxic” cause of this porphyria. Porphobilinogen synthase in lead poisoning is not diminished to such an extent as demonstrated here; in contrast to lead intoxication, porphobilinogen synthase activity cannot be activated or reactivated by thiols. All clinical and pathobiochemical data point at a new enzymatic type of endogeneous acute hepatic porphyria with intermittent acute manifestations, clinically analogous to so-called acute intermittent porphyria. Porphyrin precursors and porphyrin excretion both reflects the enzymatic defect and the regulatory consequences starting with the induction of δ-aminolevulinic acid synthase.

Inhibition of δ-aminolevulinic acid synthetase and δ-aminolevulinic acid dehydrase by L-2-amino-4-methoxy- [formula omitted]-3-butenoic acid in the rat

The rate limiting enzyme of heme biosynthesis, δ-aminolevulinic acid synthetase (ALA synthetase), and the second enzyme in the heme biosynthetic pathway, δ-aminolevulinic acid dehydrase (ALA dehydrase), were inhibited by the olefinic amino acid L-2-amino-4-methoxy - trans -3-butenoic acid (AMTB). Administration of AMTB (20 mg/kg; i.p.) to rats inhibited ALA synthetase and ALA dehydrase in control animals and in animals with markedly elevated activity of ALA synthetase which resulted from the administration of 3,5-dicarbethoxy-1,4-dimethyl-collidine (DDC, 200 mg/kg, i.p.) or allylisopropylacetamide (200 mg/kg, s.c.). AMTB also blocked the synthesis of rat hepatic porphyrins and inhibited the increase in the urinary excretion of δ-aminolevulinic acid and porphobilinogen following DDC (150 mg/kg, p.o.) administration. Preincubation of AMTB with liver mitochondria or a soluble fraction of liver decreased the activity of mitochondrial ALA synthetase and soluble ALA dehydrase, respectively.

In situ mutagenic and other effects associated with lead smelting

In situ mutagenesis and other physiologically toxic effects associated with a lead-smelting operation are measured in Zea, Tradescantia, Glycine and Peromyscus. The effects are correlated with concentrations of Pb, Cd, Cu and Zn, components of the smelter effluents, and with distance from the smelter. Increase in mutation frequency and pollen abortion is observed in Zea and Tradescantia and increase of urinary δ-aminolevulinic acid excretion is noted in Peromyscus. Decrease in height of Zea, flowering time of Tradescantia and nitrogen fixation of Glycine root are also observed.

Lead and cadmium absorption among children near a nonferrous metal plant: A follow-up study of a test case

During a first survey (1974) increased lead absorption accompanied by impaired heme biosynthesis was found among children (11 yr) attending schools situated at less than 1 km (subgroup A) and 2.5 km (subgroup B) from a lead smelter. Eighteen months after major improvements had been introduced in the factory to reduce its lead emission, a second survey (1976) was carried out in the same schools (lead smelter and rural area) on other groups of children which were comparable with those of the first survey. The continuous air monitoring revealed for the lead smelter area a considerable decrease in airborne lead. The median values dropped from 3.2 to 1.2 μg Pb/m 3 at less than 1 km and from 1.6 to 0.5–0.8 μg Pb/m 3 at 1.5 km from the plant; in the rural area it remained unchanged at 0.3 μg Pb/m 3. In order to evaluate the efficiency of the technological improvements we assessed the lead and cadmium exposure of the children by measuring lead concentration in blood (PbB) and urine (PbU), erythrocyte δ-aminolevulinic acid dehydratase (ALAD) activity, free erythrocyte porphyrin (FEP) concentration, δ-aminolevulinic acid excretion in urine (ALAU), and cadmium concentration in blood (CdB) and urine (CdU). Subgroups A and B exhibited higher PbB and CdU levels, and lower ALAD activity than the rural group; but PbU, CdB, FEP, and ALAD were significantly increased only in subgroup A. Compared with the results of the first survey, a significant tendency to a normalization of PbB was found at 2.5 km, but at less than 1 km the biological parameters (particularly PbB, ALAD, FEP) did not improve. The PbB percentile distribution in subgroup B lies now under the tentative PbB percentile distribution proposed in the PbB Directive of the Commission of the European Communities (CEC): that of subgroup A, however, is still above that of the CEC proposal. Taking into account the higher degree of vulnerability to lead exposure as compared to adults a more restrictive PbB percentile distribution has been proposed for children. Two hypotheses have been put forward to explain the lack of significant improvements in the biological parameters of the children living at less than 1 km from the lead smelter. Ingestion of dust and dirt (probably due to hand contamination) from their surroundings in the course of their normal everyday activity may represent, in addition to air, a supplementary cause of increased lead accumulation in these children. Indeed, dust and dirt samples collected on the school playgrounds at less than 1 km from the factory contained (mean ± SD) 3541 ± 1310 and 5466 ± 831 μg Pb/g, whereas at 2.5 km and in the rural area it only amounted to 397 ± 33 and 152 ± 41 μg Pb/g, respectively. The alternative explanation is that a continuous resuspension of dust and dirt particles from the highly contaminated soil around the lead smelter may maintain a very high airborne lead concentration at the breathing height of the children. In addition to a lasting reduction of lead emission from the plant, the remedial actions should also take into consideration these two possibilities.

Antagonistic effect of zinc on increased urine δ-aminolevulinic acid excretion in lead-intoxicated rats

Urine δ-aminolevulinic acid (ALAU) excretion has previously been reported as being closely correlated with the clinical picture of lead poisoning. In the present investigation, rats were administered either zinc or lead or both. Zinc administration resulted in the reduction to near normal levels of ALAU excretion in lead-intoxicated rats. This effect occurred in the absence of any significant reduction in blood lead levels or any alleviation of the anemia of lead toxicity. The observations place considerable doubt on the validity of using ALAU screening tests as a means of determining lead exposure.

Effects of concurrent administration of lead, cadmium, and arsenic in the rat

Humans are exposed to a number of toxic elements in the environment; however, most experiments with laboratory animals investigate only one toxic element. To determine if concomitant exposure to lead (Pb), cadmium (Cd), and/or arsenic (As) modified the changes produced by any one metal in various parameters of toxicity, 168 male, Sprague-Dawley, young adult rats were fed nutritionally adequate diets to which had been added 0 or 200 ppm Pb as Pb acetate, or 50 ppm Cd as Cd chloride, or 50 ppm As as sodium arsenate or arsanilic acid in a factorial design for a period of 10 weeks. At these concentrations, Cd and As reduced weight gain even when differences in food intake were taken into account; administration of both Cd and As depressed weight gain more than did either metal alone. Pb did not adversely affect food consumption or weight gain. Increased numbers of red blood cells (RBCs) were observed following administration of Pb, Cd, or As; usually more cells were observed when two or three metals were administered, compared to individual metals. Despite increasing numbers of circulating RBCs, hemoglobin and hematocrit were reduced, especially with the Pb-Cd combination and the Cd-arsanilic acid combination. Specific effects of Pb on heme synthesis were observed, including increased urinary excretion of delta-aminolevulinic acid; this increase was reduced by the presence of dietary cadmium. Analyses of blood showed values for the laboratory rat within normal ranges for blood urea nitrogen, creatinine, cholesterol, calcium, albumin, total protein, and bilirubin. Uric acid was increased by Pb, with little modification by dietary Cd or As content. Serum glutamate-oxalate transaminase activity was reduced by As. Serum alkaline phosphatase was greatly reduced by either As or Cd but not Pb. Combinations of As and Cd did not further reduce the activity of this enzyme. Kidney weight and kidney weight/body weight ratios were increased by Pb alone, with no effects of Cd or As alone or as interactions. Liver weight/body weight ratios were reduced in animals fed 50 ppm dietary Cd. Kidney histology shows predominantly Pb effects, namely, intranuclear inclusion bodies and cloudy swelling. Ultrastructural evaluation of kidneys from Pb-treated animals disclosed nuclear inclusion bodies of the usual morphology and mitochondrial swelling. Concurrent administration of Cd greatly minimized Pb effects on the kidney under conditions of this experiment. Liver histology suggests an increased rate of cell turnover with either As compound, but few specific changes.

Plumbism from airborne lead in a firing range: An unusual exposure to a toxic heavy meta

Plumbism developed in a 17 year old boy while he was working in an indoor firing range. Diagnosis was delayed because a blood lead level was initially reported to be within normal limits and because acute intermittent porphyria was suspected. Subsequently, lead poisoning was clearly documented by characteristic abnormalities of the heme biosynthetic pathway in erythrocytes (inhibited δ-aminolevulinic acid dehydratase activity, increased protoporphyrin-IX), increased urinary excretion of δ-aminolevulinic acid and coproporphyrin, and elevated levels of lead in blood and urine. These abnormalities as well as decreased nerve conduction velocity and reduced hepatic cytochrome P-450 function, as assessed by metabolism of antipyrine, returned towards normal with chelation therapy. Investigation of the firing range showed airborne lead to be markedly increased during firing; a co-worker was also found to have asymptomatic lead poisoning. This experience shows that exposure to heavy metals can occur by mechanisms which are unusual and not widely recognized, and illustrates the importance of testing erythrocytes and urine for distinct biochemical abnormalities related to the heme synthetic pathway when differentiating hereditary hepatic porphyria from plumbism.

Hexachlorobenzene exposure from contaminated DCPA in vegetable spraymen.

Hexachlorobenzene (HCB) blood residues were found in 19 of 20 vegetable spraymen exposed to HCB-contaminated dimethyl-1-2, 3, 5, 6-tetrachloroterephthalate (DCPA). The mean level was 40 ± 63 parts per billion (ppb) with a range of 0 to 310 ppb. No definite physical or biochemical effects of this exposure were discovered. Specifically there was no evidence of cutaneous porphyria or abnormalities of uroporphyrin or coproporphyrin excretion. A positive correlation (P<.05) was found for HCB levels and δ-aminolevulinic acid excretion but this was interpreted skeptically.

A modification of the berkó-durkó method for the determination of δ aminolevulinic acid in urine

The Berkó—Durkó method for the determination of δ-aminolevulinic acid in urine operates under suboptimal conditions. The author has developed a modification of this method which gives improved sensitivity and high reproducibility, by lowering and buffering the pH of the diluting solution. Normal 24-h δ-aminolevulinic acid excretion values acquired with the modified procedure are presented.

The effect of DL-propranolol on γ-aminolevulinic acid synthetase activity and urinary excretion of porphyrins in allylisopropylacetamide-induced experimental porphyria

Experimental porphyria was induced in rats by allylisopropylacetamide. DL-Propranolol, a β-adrenergic-receptor blocking agent, significantly reduced the elevated urinary excretion of δ-aminolevulinic acid, porphobilinogen and total porphyrins. DL-Propranolol also partially prevented the increased activity of δ-aminolevulinic acid synthesis in liver homogenates of allylisopropylacetamide-treated rats. It had no effect on the above parameters in normal rats. These findings support the hypothesis that δ-aminolevulinic acid exists in two forms, a constitutive and an inducible one. In order to examine whether the action of the drug was caused by its membrane effect. D-propranolol and quinidine sulphate were used in similar sets of experiments. These drugs had no effect on the abnormal porphyrin metabolism of allylisoprpyl-acetamide-treated rats, indicating that the results obtained with DL-propranolol were not due to its membrane action.

Effect of lead on blood regeneration following acute hemorrhage in dogs.

Thirty-six beagle dogs were divided into three hematologically similar groups of six males and six females each. The dogs of one group acted as controls and were fed only the basic diet. The dogs of the other two groups had lead acetate added to their diets, those of one group receiving 100 ppm of lead by weight, those of the other group, 500 ppm for 30 weeks followed by 1000 ppm for 16 weeks. By the end of 46 weeks, both lead-treated groups had accumulated burdens of lead as demonstrated by increases in blood and urine lead concentrations, increased urine δ-aminolevulinic acid excretion, and decreased red cell ALA dehydrase activity. At this time a two-step withdrawal of one-half the estimated blood volume from each dog resulted in a 30 to 40% reduction in hemoglobin concentration, red cell count, and hematocrit ratio. The recoveiy curves of the hemoglobin concentration, red cell count, and hematocrit ratio were not affected by the presence of the lead.

鉛中毒ラットのポルフィリン代謝におよぼすエタノールの影響について

On the effect of ethanol administration on porphyrin metabolism in rats intoxicated with lead acetate, the urinary excretion of δ-aminolevulinic acid and coproporphyrin was determined, and the activity of δ-aminolevulinic acid produced in rats liver homogenate was measured. The following results were obtained.1) The urinary excretion of coproporphyrin and δ-aminolevulinic acid in rats intoxicated with lead acetate was increased by ethanol treatment.2) It was demonstrated that the hepatic δ-aminolevulinic acid producing activity in rats intoxicated with lead acetate was additively enhanced by ethanol treatment.3) The activation of hepatic δ-aminolevulinic acid producing activity with ethanol was inhibted by pre-treatment of pyrazole.

The influence of iron deficiency on tissue content and toxicity of ingested lead in the rat.

Abstract Lead poisoning in young children is often associated with iron deficiency anemia. The relationship of this dietary deficiency to enhancement of lead toxicity has not been documented. In the present study, a subtoxic dose of lead (200 μg per milliliter of drinking water) was fed to rats receiving a purified diet containing adequate iron (25 p.p.m.), calcium, and phosphorus, and a diet deficient only in iron (5 p.p.m.) for 10 weeks. Iron deficiency resulted in an increased retention of lead in liver, kidney, and bone, and increased urinary excretion of lead. Biochemical parameters of lead toxicity including urinary excretion of δ-aminolevulinic acid were greater in iron-deficient rats fed lead than in rats receiving adequate diets and lead. The metabolic basis for the enhancement of lead retention and toxicity by iron deficiency is not known, but may result from increased lead absorption and transport.

Occupational exposure to inorganic compounds of lead. Investigation of -aminolevulinic acid and coproporphyrin excretion rates of persons exposed occupationally for the first time.

The contamination of a large area in Yugoslavia by lead from a mine and smelter (which have operated for centuries) is illustrated in a preliminary report by fragmentary data obtained by the determination of lead in the surrounding air, in the water of a river draining the area, in the soil, and in local vegetation. A screening test (determination of the urinary excretion of δ-aminolevulinic acid) applied to groups in the population suggests that the absorption of lead by members of the groups may be hazardous.

Vitamin E and porphyrin metabolism in man.

Four patients with symptoms of porphyria were treated with water soluble vitamin E. In all four patients, urinary excretion of δ-aminolevulinic acid, porphobilinogen, coproporphyrins, and uroporphyrins, which were initially elevated, decreased to normal levels following therapy. The initial vitamin E levels in whole blood which were lower than normal responded to treatment with the vitamin and paralleled clinical improvement. The effects of vitamin E on porphyrin metabolism were examined in a group of six male chronic alcoholic patients without clinical evidence of chronic liver disease. The coproporphyrinuria associated with alcoholism was found to be nonresponsive to vitamin E. Our observations indicate that the action of vitamin E in porphyria is probably not mediated through a reversal of the effects of any concurrent alcoholism.

The effect of vitamin E on porphyrinuria induced by ethanol in the rat

The effect of vitamin E administration on increased urinary excretion of porphyrins and porphyrin precursors induced by ethanol administration was studied in rats. Increases in the urinary excretion of δ-aminolevulinic acid, porphobilinogen, and coproporphyrins occurred in rats fed ethanol for a period of 14 days. The administration of vitamin E prevented the ethanol-induced increases in the urinary excretion of coproporphyrins but not of δ-aminolevulinic acid and porphobilinogen. Activities of hepatic δ-aminolevulinate synthase and δ-aminolevulinate dehydratase were not found to be enhanced when the ethanol-fed rats were sacrificed after 12 hours of fasting. Vitamin E administration did not prevent the induction of cytochrome P-450 by ethanol. The specific interference of vitamin E administration with the ethanol-induced increases in the urinary excretion of coproporphyrins remains unexplained.

Induction of Hepatic δ-Aminolevulinic Acid Synthetase by Oral Contraceptive Steroids

ABSTRACT The ability of oral contraceptive steroids to induce the hepatic enzyme, δ-aminolevulinic acid synthetase (ALAS), has been examined in vivo in a model test system utilizing 15- to 16-day-old chick embryos. ALAS controls the rate-limiting step in the biosynthesis of porphyrins and heme. All the progestational components of the contraceptive mixtures studied had potent ALAS inducing activity except for chlormadinone acetate. The inducing capacity of the different progestational agents varied, but all showed positive dose-response relationships. Neither of the estrogenic components of the oral contraceptives, mestranol or ethinyl estradiol, induced the enzyme significantly by itself, nor did these estrogens alter the degree of induction by the progestational compounds. The possible relevance of these findings to the increased urinary excretion of δ-aminolevulinic acid reported in some normal women receiving oral contraceptives, and to the experimental hormonal therapy of selected patients with acute...

Tryptophan pyrrolase, tryptophan and tyrosine transaminase changes during allylisopropylacetamide-induced porphyria in the rat

Changes in liver tryptophan pyrrolase (EC 1.11.1.4) and in tyrosine and tryptophan transaminase (EC 2.6.1.5) activities after induction of experimental porphyria with allylisopropylacetamide (AIA) were studied in female rats of the Long-Evans strain. All three enzymic activities increased after a single injection of AIA (400 mg/kg) to intact animals. AIA treatment also increased tryptophan pyrrolase in adrenalectomized but not in hypophysectomized animals. Peak levels of enzyme were reached in about 8 hr after drug administration to intact animals. The magnitude of the change in intact animals was enhanced by a 16-hr fast preceding the AIA treatment. Acute administration of AIA also produced behavioral changes and increased urinary excretion of δ-aminolevulinic acid and porphobilinogen. Behavioral, enzymic and excretory changes produced by the drug progressively diminished in magnitude with continued drug treatment.

Excretion of δ-aminolevulinic acid in hereditary tyrosinemia

In two subjects with hereditary tyrosinemia attacks of severe pains in the abdomen and legs and pareses of peripheral type have been observed. The similarity of these attacks with the crises seen in acute intermittent porphyria prompted us to measure the excretion of δ-aminolevulinic acid, porphobilinogen and porphyrins in these patients and in 4 other patients with hereditary tyrosinemia. The urinary excretion of δ-aminolevulinic acid was from 10 to 250 mg per g of creatinine, i.e., up to a 100-fold increase above the normal range. The excretion of porphobilinogen and porphyrins fell within the normal ranges or was only slightly elevated.

Urinary excretion of aminoacetone following administration of L-threonine in man.

A glucose diet and complete starvation resulted in a 30–40 per cent decrease of the urinary aminoacetone in man, whereas the excretion of δ-amino-levulinic acid remained unchanged. Oral and parenteral administration of L-threonine significantly enhanced the urinary excretion of aminoacetone. Threonine loading also produced a slight increase in the excretion of glycine, but no change in the excretion of δ-aminolevulinic acid.