RESUMEN
Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I(Kr)), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.
Asunto(s)
Diseño de Fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genética , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/genética , Potenciales de Acción/efectos de los fármacos , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Corazón/fisiología , Humanos , Síndrome de QT Prolongado/metabolismo , Modelos Moleculares , Mutación , Canales de Potasio con Entrada de Voltaje/química , Torsades de Pointes/inducido químicamenteRESUMEN
The majority of drugs associated with QT interval prolongation share an ability to inhibit ionic currents passed by HERG potassium channels. One method of screening new chemical entities (NCEs) for QT prolonging potential is therefore to use heterologous systems expressing HERG channels. Such systems are also of value in the understanding of the function, kinetics, sorting, pharmacological sensitivities, and important molecular determinants of the HERG potassium channel. The methods for incorporating the HERG potassium channel into cells and measuring the consequent current are a mixture of techniques that are standard (for heterologous expression of most ion channels) and individualised to HERG. This review presents a selection of the most commonly used methods for examining heterologous HERG currents, as well as introducing some of the technical problems that may be encountered and their solutions. In mammalian cell lines, problems such as fragile membranes, high leak currents, inability to form a gigaseal, diminished HERG current, endogenous transient outward current, altered kinetics, and even occasional run down can interfere with measurements. In Xenopus oocytes, endogenous chloride currents, insufficient superfusate flow, diminished HERG current and HERG current 'run up' may create difficulties.