Effects of volatile anaesthetics on heme metabolism in a murine genetic model of Acute Intermittent Porphyria. A comparative study with other porphyrinogenic drugs (original) (raw)
Related papers
European Journal of Biochemistry, 1994
Mifepristone (RU-486), a potent progesterone receptor antagonist and inducer of cytochromes P-450, is currently in use in Europe, particularly as a post-coital oral contraceptive. Soon it will be available in the United States, as well. Since progesterone has been implicated in the pathogenesis of acute attacks of porphyria, the use of RU-486 or related compounds might be considered in porphyric patients. However, as with other cytochrome P-450 inducers, RU-486 may have the ability to precipitate or exacerbate attacks of acute porphyria. The acute porphyrias in relapse are associated with an increase in activity of 8-aminolevulinic acid synthase, the first and normally rate-controlling enzyme in heme biosynthesis. We have used primary cultures of chick embryo liver cells to test the ability of RU-486 to induce b-aminolevulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin accumulation, and heme oxygenase. We found that RU-486, at concentrations observed in human plasma after a single oral dose, induced the mRNA and activity of b-aminolevulinic acid synthase, both by itself and in the presence of deferoxamine, a potent iron chelator that inhibits ferrochelatase. RU-486 and deferoxamine together also produced significant accumulations of protoporphyrin. These results indicate that RU-486 may pose a risk in patients with known acute porphyria and should be used with caution. RU-486 increased the concentration of total cytochrome P-450, and the activity of erythromycin demethylase, an activity specifically catalyzed by cytochrome P-450 3A. Unlike several other porphyrogens (e.g. hydantoins, barbiturates), RU-486 does not produce accumulation of uroporphyrin or induction of heme oxygenase in chick embryo liver cells.
PK 11195 aggravates 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic porphyria in rats
Hepatology, 1996
of the heme biosynthetic pathway. Porphyrias are classified There is evidence to suggest that peripheral-type beninto two main categories: hepatic or erythropoietic, dezodiazepine receptors (PBR) are involved in porphyrin pending on whether the excessive porphyrin production is in transport during erythroid differentiation, and it is posthe liver or in the bone marrow, respectively. 3,4 sible that these receptors have an important role in Some chemical agents and drugs can produce biochemical heme biosynthesis. We examined the biochemical and disorders in rats that resemble different forms of human heultrastructural alterations in rat liver following experipatic porphyria. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine mentally induced acute hepatic porphyria, as well as the (DDC) is a fast-acting synthetic compound that is frequently effects of the administration of a selective PBR ligand, used to produce experimental hepatic porphyria in fasting PK 11195. The most severe pathological conditions were rats. 5 The fasting state of the rats is a necessary factor to found in rats that received a combined treatment of the induce the porphyrinogenic effect of DDC, and is termed the porphyrinogenic agent 3,5-diethoxycarbonyl-1,4-dihy-''glucose effect.'' 6 DDC causes the accumulation of a green drocollidine (DDC) and PK 11195. Transmission electron porphyrin-like pigment, N-methylprotoporphyrin IX, which microscopy showed a correlation between the ultrais a potent inhibitor of the enzyme ferrochelatase, which constructural pathology of the liver, the total porphyrin levverts protoporphyrin IX into heme in the heme biosynthetic els in urine and liver, and the porphobilinogen levels in pathway. 7,8 DDC causes greatly increased levels of hepatic urine. Hepatocytes in this acute porphyria showed the protoporphyrin IX and increased levels of urinary excretion of development of large secondary lysosomes containing porphobilinogen (PBG) and d-aminolevulinic acid in a pattern crystalline aggregates of protoporphyrin. Bile canaliculi similar to that of an acute attack of human variegate porwere grossly enlarged, contained aggregates of protophyria. 5 Variegate porphyria is an acute porphyria in which porphyrin crystals, and showed the presence of bile protoporphyrinogen oxidase activity is lowered, and in which thrombi. In addition, prominent bundles of collagen fiprotoporphyrin IX consequently becomes the major circulatbers (fibrosis) were commonly found in livers of rats that ing porphyrin. 3 had been treated with DDC or DDC and PK 11195. We Benzodiazepines (BZ) have anxiolytic, anticonvulsant, conclude that the administration of PK 11195 to pormuscle-relaxant, and hypnotic properties. These therapeutic phyric rats aggravates porphyrin accumulation and celresponses are mediated by the central BZ receptors, abunlular damage in the liver. Perhaps this evidence suggests dant in the central nervous system, and are coupled with gthat PK 11195 blocks the binding of protoporphyrin IX aminobutyric acid receptors and the chloride ion channel. 9 to PBR, thus elevating the content of protoporphyrin IX In addition, BZs bind to peripheral BZ receptors (PBR), which in liver. (HEPATOLOGY 1996;24:697-701.) have been identified in various peripheral tissues as well as in glial brain cells. 10-13 PBR are located mainly in the outer Porphyrins, except for protoporphyrin IX, an intermediate mitochondrial membrane, 14 although they have been found in heme biosynthesis, are by-products that have escaped the in red blood cells, which lack mitochondria. 15 The BZ ligand pathway of heme biosynthesis through irreversible oxidation Ro 5-4864, as well as the isoquinoline carboxamide derivative of the corresponding porphyrinogens. 1,2 The porphyrias are PK 11195, demonstrates a high affinity for PBR. 16 a group of inherited or acquired diseases resulting from over-Displacement experiments of [ 3 H]PK 11195 binding, from production, accumulation, and excretion of excessive porphy-PBR located on various peripheral tissues, with porphyrins rins, and their precursors are secondary to enzymatic defects and hemin have been performed. 17 It was found that pure in the heme biosynthetic pathway. At least seven different hemin and protoporphyrin IX competitively inhibit mitochonporphyrias exist, a result of specific defects in the enzymes drial BZ binding with inhibition constants of 41 and 15 nmol/ L, respectively. Therefore, it was concluded that dicarboxylic acid porphyrins appear to be endogenous ligands for PBR. Recently, it has been found that PBR appear to be involved Abbreviations: DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; PBG, porphobilinogen; in porphyrin transport during erythroid differentiation. 18 BZ, benzodiazepines; PBR, peripheral-type benzodiazepine receptors; DMSO, dimethyl sulf-Consequently, PBR may play an important role in the eryoxide. throid-specific induction of heme biosynthesis. 18
Brazilian Journal of Medical and Biological Research, 2002
We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of d-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, d-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme d-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.
Toxicology, 2011
This work deals with the study of how porphyrinogenic drugs modeling acute porphyrias interfere with the status of carbohydrate-regulating hormones in relation to key glucose enzymes and to porphyria, considering that glucose modulates the development of the disease. Female Wistar rats were treated with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) using different doses of AIA (100, 250 and 500 mg/kg body weight) and a single dose of DDC (50 mg DDC/kg body weight). Rats were sacrificed 16 h after AIA/DDC administration. In the group treated with the highest dose of AIA (group H), hepatic 5-aminolevulinic acid synthase (ALA-S) increased more than 300%, phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP) activities were 43% and 46% lower than the controls, respectively, plasmatic insulin levels exceeded normal values by 617%, and plasmatic glucocorticoids (GC) decreased 20%. GC results are related to a decrease in corticosterone (CORT) adrenal production (33%) and a significant reduction in its metabolization by UDP-glucuronosyltransferase (UGT) (62%). Adrenocorticotropic hormone (ACTH) stimulated adrenal production 3-fold and drugs did not alter this process. Thus, porphyria-inducing drugs AIA and DDC dramatically altered the status of hormones that regulate carbohydrate metabolism increasing insulin levels and reducing GC production, metabolization and plasmatic levels. In this acute porphyria model, gluconeogenic and glycogenolytic blockages caused by PEPCK and GP depressed activities, respectively, would be mainly a consequence of the negative regulatory action of insulin on these enzymes. GC could also contribute to PEPCK blockage both because they were depressed by the treatment and because they are positive effectors on PEPCK. These disturbances in carbohydrates and their regulation, through ALA-S de-repression, would enhance the porphyria state promoted by the drugs on heme synthesis and destruction. This might be the mechanism underlying the "glucose effect" observed in hepatic porphyrias. The statistical correlation study performed showed association between all the variables studied and reinforce these conclusions.
Journal of pharmacological methods, 1981
Rat liver tryptophan pyrrolase plays a versatile and unique role among hepatic hemoproteins in relation to heme utilization. The depletion of pyrrolase heme in the experimental porphyria produced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine is potentiated by joint administration of any one of 19 drugs known to exacerbate the human disease, but not by any of 13 nonexacerbators. These findings form the basis of a screening test for drug exacerbation of hepatic porphyrias; the conditions, details, and requirements of which are described.
PLoS ONE, 2012
Chronic kidney disease is a long-term complication in acute intermittent porphyria (AIP). The pathophysiological significance of hepatic overproduction of the porphyrin precursors aminolevulinate acid (ALA) and porphobilinogen (PBG) in chronic kidney disease is unclear. We have investigated the effect of repetitive acute attacks on renal function and the effect of total or five-sixth nephrectomy causing renal insufficiency on hepatic heme synthesis in the porphobilinogen deaminase (PBGD)-deficient (AIP) mouse. Phenobarbital challenge in the AIP-mice increased urinary porphyrin precursor excretion. Successive attacks throughout 14 weeks led to minor renal lesions with no impact on renal function. In the liver of wild type and AIP mice, 5/6 nephrectomy enhanced transcription of the first and rate-limiting ALA synthase. As a consequence, urinary PBG excretion increased in AIP mice. The PBG/ALA ratio increased from 1 in sham operated AIP animals to over 5 (males) and over 13 (females) in the 5/6 nephrectomized mice. Total nephrectomy caused a rapid decrease in PBGD activity without changes in enzyme protein level in the AIP mice but not in the wild type animals. In conclusion, high concentration of porphyrin precursors had little impact on renal function. However, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.
Biochemistry
Patients with major forms of acute hepatic porphyria present acute neurological attacks with overproduction of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA). Even if ALA is considered the most likely agent inducing the acute symptoms, the mechanism of its accumulation has not been experimentally demonstrated. In the most frequent form, acute intermittent porphyria (AIP), inherited gene mutations induce a deficiency in PBG deaminase; thus, accumulation of the substrate PBG is biochemically obligated but not that of ALA. A similar scenario is observed in other forms of acute hepatic porphyria (i.e., porphyria variegate, VP) in which PBG deaminase is inhibited by metabolic intermediates. Here, we have investigated the molecular basis of δ-aminolevulinate accumulation using in vitro fluxomics monitored by NMR spectroscopy and other biophysical techniques. Our results show that porphobilinogen, the natural product of δaminolevulinate deaminase, effectively inhibits its anabolic enzyme at abnormally low concentrations. Structurally, this high affinity can be explained by the interactions that porphobilinogen generates with the active site, most of them shared with the substrate. Enzymatically, our flux analysis of an altered heme pathway demonstrates that a minimum accumulation of porphobilinogen will immediately trigger the accumulation of δ-aminolevulinate, a long-lasting observation in patients suffering from acute porphyrias.
Anesthetic implications in porphyrias
Frontiers in Anesthesiology
The porphyrias are a group of disorders related to deficient heme biosynthesis, caused by malfunction of certain enzymes in the synthesis pathway. Erythropoietic porphyrias present with cutaneous symptoms and do not affect the nervous system. Hepatic porphyrias develop acute attacks with mild to severe neurovisceral symptoms, dramatic course, and rare, but possibly lethal outcomes. Anesthetic management of patients suffering from hepatic porphyria is challenging regarding the possibility of triggering or worsening the acute attack with medications that induce or maintain anesthesia. The medications are labeled as safe or unsafe according to laboratory experiments, clinical studies, case reports and experience. In this paper, we discuss underlying pathophysiology, presentation, therapy recommendations and anesthetic implications related to porphyrias.