Gene-environmental interactions: Lessons from porphyria

Sassa, Shigeru

doi:10.1007/bf02908884

Cited by 5 publications

(5 citation statements)

References 27 publications

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“…34 It is well known that drugs are one of the most important precipitating factors of acute porphyric attacks, so that the acute porphyrias are also considered to be pharmacogenetic or toxicogenetic diseases. 8,34,35,38 The capacity of a drug to induce an APA (ie, drug porphyrogenicity) depends mostly on its ability to directly activate the synthesis of ALA-S1 or to block its negative regulatory feedback control by reducing the hepatic free heme pool ( Figure 2). 7…”

Section: Drugs and Acute Porphyrias: A Hazardous Relationshipmentioning

confidence: 99%

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Roveri

Nascimbeni

Rocchi

et al. 2014

Postgraduate Medicine

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The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic "bottleneck" in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.

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Section: Drugs and Acute Porphyrias: A Hazardous Relationshipmentioning

confidence: 99%

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Roveri

Nascimbeni

Rocchi

et al. 2014

Postgraduate Medicine

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“…Participants are given the option to share this survey with family members and friends, both those with and without porphyria symptoms. Although family members and friends without symptoms at the time of the survey will likely never develop symptoms (due to the low penetrance of porphyria-associated mutations), we seek to identify modifying genes and environmental factors that contribute to the phenotype through comparing genotypes of these individuals with those of people reporting latent and active porphyria 64 . We plan to explore the possibility of recruiting participants by adding UPWARD links to the SNPedia research database, as well as through collaborating with porphyria advocacy and patient-education groups, and clinical partners.…”

Section: Project Descriptions and Goalsmentioning

confidence: 99%

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

et al. 2019

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Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich’s Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, “Iron Hack” participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

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“…74 Ultimately, haem levels are dependent on the rate of synthesis versus degradation and can vary between tissues. 75…”

Section: Regulatory Mechanisms Of Haem Supplymentioning

confidence: 99%

“…98 In addition, most steroid hormones require P450s for their synthesis and from the clinical prospective there is evidence that steroid hormones are important precipitation factors of porphyria attacks. 75 About 80% of AIP patients are female and it also uncommon before puberty or after menopause which suggest that the adult levels of female hormones are key in the regulation of haem synthesis. The identification of single nucleotide polymorphism in the promoter region of ALAS1 in porphyria variegate patients have revealed the presence of an oestrogen receptor α binding site.…”

Section: D Regulation By Exogenous and Endogenous Agentsmentioning

confidence: 99%

Complicity of haem in some adverse drug-reactions

Vágány

Smith

2015

Toxicol. Res.

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Adverse drug reactions are often idiosyncratic responses to administered medicines or herbal remedies that may be the consequence of multiple interactions between physiological and genetic factors with drug target and off-target effects. Identification and resolution of the mechanisms of these factors for individuals can prove problematic. Genetic variants or acquired fluctuations in the activity of the haem metabolism enzymes are well established predisposition factors in some known clinical hepatic disorders.Some of these disorders of nonerythroid haem supply can be triggered by drugs, hormones and other agents that normally have no untoward effects. Thus these mutations affecting the activity of the enzymes in the haem pathway can be regarded as predisposing genetic factors causing adverse reactions of some drugs in susceptible individuals. Carriers may be non-symptomatic for a prolonged period until the combination of factors such as consumption of medicinal products, alcohol, stress, hormone fluctuations and change in dietary habits trigger clinical symptoms. Despite these inherited or acquired changes of the haem metabolic pathway, many carriers do not develop symptoms illustrating the involvement of other unknown genetic components. In addition, haem is of fundamental cellular importance not only for respiratory cytochromes and oxygen transport but for many other roles such as for cytochrome P450, NO signalling, and microRNA formation. For these reasons, nonerythroid haem synthesis is under complex transcriptional and translational regulation linked to age, nutrition and circadian rhythm and to hormonal, drug and stress responses. Besides those already known, interference and genetic differences in the flux of supply, recruitment and use of haem for such fundamental processes may contribute to adverse drug reactions in metabolic arenas that are not yet recognised.

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Gene-environmental interactions: Lessons from porphyria

Cited by 5 publications

References 27 publications

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

Complicity of haem in some adverse drug-reactions

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