Strategies for Avoiding Benzopyrone Hepatotoxicity in Lymphedema Management-The Role of Pharmacogenetics, Metabolic Enzyme Gene Identification, and Patient Selection.
Lymphat Res Biol
; 15(4): 317-323, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-29087786
ABSTRACT
INTRODUCTION:
Benzopyrones are plant-derived chemicals which have an evidenced degree of clinical efficacy in lymphedema management indicated in past trials. Unfortunately, in some of these cases idiosyncratic hepatotoxicity have been documented in a minority of patients. This review aims to tackle the problem of benzopyrone (particularly coumarin) toxicity by considering their metabolic pathways and identifying relevant alleles needed to take a targeted pharmacogenetic approach in its future use. METHODS ANDRESULTS:
The nontoxic 7-hydroxylation and the toxic heterocyclic "ring-splitting" epoxidation pathways are the two main detoxification pathways in the hepatometabolism of coumarin, the former catalyzed by CYP2A6 and the latter by possibly CYP1A and CYP2E. Acetaldehyde dehydrogenase (ALDH) clears toxic aldehyde intermediates. CYP2A6 polymorphism screening methods, including genotyping, by real-time polymerase chain reaction and chromatography-mass spectroscopy functional metabolite assays; efficiency of these techniques are continually improving. ALDH polymorphisms have also been implicated, with clinically viable screening tests, rapid genotyping, and sensitive questionnaires already available for ALDH2*1/ALDH2*2. Dysfunctional polymorphisms of the above genes and others are significantly more prevalent in Eastern Asian populations, uncommon in Caucasian populations. The role of other enzymes/genes in the pathway is yet to be clarified.CONCLUSION:
Although screening techniques are becoming increasingly clinically feasible, uncertainty remains on the link between the genotype, metabolic phenotype, and the exact gene products involved. These must be elucidated further before a targeted pharmacogenomic approach is fully viable. In the meantime, treatment should be avoided in those with vulnerable familial and ethnic descents if used.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Farmacogenética
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Benzopirenos
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Regulação Enzimológica da Expressão Gênica
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
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Variantes Farmacogenômicos
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Linfedema
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article