CYP2D6 Polymorphisms in Patients with Porphyrias

Lavandera, Jimena Verónica; Parera, Victoria Estela; Batlle, Alcira; Buzaleh, Ana Maria

doi:10.2119/2005-00047.lavandera

Cited by 8 publications

(5 citation statements)

References 29 publications

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“…Variations in CYP2D6 have been associated with a vast list of diseases (e.g., arterial hypertension, 12 leukemia, 13 childhood apnea, 13 thyroid cancer, 14 Alzheimer disease and Parkinson disease, [15][16][17][18][19] hepatic disease, 20 pulmonary disease, 21,22 breast cancer, 23 porphyrias 24 ) and with people's ability to metabolize antidepressants. 25 To date, up to 75 different alleles have been reported for CYP2D6 (descriptions available at www .imm.ki .se/cypalleles); more than 15 of these encode an inactive isoform or no enzyme, whereas other variations consist of gene duplications.…”

Section: Cytochrome P450mentioning

confidence: 99%

Pharmacogenetics of Antidepressant Response

Serretti

Drago

Liebman

2008

Biomarkers for Psychiatric Disorders

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Personalized medicine-the adaptation of therapies based on an individual's genetic and molecular profile-is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

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Section: Cytochrome P450mentioning

confidence: 99%

Pharmacogenetics of Antidepressant Response

Serretti

Drago

Liebman

2008

Biomarkers for Psychiatric Disorders

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“…It is also of great interest to recognize how the genetic background may modulate the penetrance, making personalized genetic counselling and health care more feasible. To date, a high prevalence of specific CYP alleles in some types of porphyria has been described compared to that observed in a healthy population, suggesting that they might be susceptibility factors [20–22]. The present study provides further evidence that CYP genes may constitute penetrance-modifying factors in AIP, since CYP2D6*4 and *5 were more frequent in LAIP than in MAIP, although their allelic frequencies were similar in whole AIP carriers and the general population [27].…”

Section: Discussionmentioning

confidence: 99%

“…A high frequency of two polymorphisms in CYP1A2 and CYP1A1 genes has been reported in porphyria cutanea tarda, both polymorphisms being associated with increased enzymatic activity [20, 21]. In addition, non-functional CYP2D6*3 and *4 alleles seemed to be less frequent in AIP carriers compared to a control population [22].…”

Section: Introductionmentioning

confidence: 99%

High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor

Barreda‐Sánchez

Buendía-Martínez

Glover-López

et al. 2019

Orphanet J Rare Dis

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Background Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10–20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2 , *3 ; CYP2C19*2 ; CYP2D6*4 , *5 ; CYP3A4*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669_698del30. Results AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers ( p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype. Conclusions AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.

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“…66 For example, the differences in hepatic polymorphisms of CYPs could explain why acute attacks can be triggered by a certain drug in some individuals, whereas others are resistant to exposure to the same unsafe drug; only a single study has explored this hypothesis in patients with acute porphyrias. 67 Nevertheless, the problem remains very complex, because it is not only liver cytochromes that are involved in determining the susceptibility to porphyrogenic agents, but also those present in other tissues (mitochondrial and microsomal the treatment of the disturbance per se and in prescribing drugs). Practitioners should by refer to systematic operative databases or to expert centers when treating these patients.…”

Section: Nonacute Porphyriasmentioning

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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CYP2D6 Polymorphisms in Patients with Porphyrias

Cited by 8 publications

References 29 publications

Pharmacogenetics of Antidepressant Response

Pharmacogenetics of Antidepressant Response

High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

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