Polymorphisms Affecting Drug Receptors And Targets

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Many drugs interact with specific targets such as receptors, enzymes and other proteins involved with cell cycle control, signal transduction and other cellular events. Genes encoding these targets occur in polymorphic forms that may alter their pharma-cologic response to specific medicines. For example, variants affecting ^-adrenergic receptors are a major determinant of ,-agonist bronchodilator (e.g. albuterol) response in asthmatic patients. A specific common polymorphism has been linked to increased ,3-2 receptor down-regulation in response to treatment with albuterol, which may result in decreased drug efficacy and duration of action (Tan et al., 1997; Liggett, 2000). However, other studies have failed to show the expected correlation between the variant and clinical response (Lipworth et al., 1999). Drysdale et al. (2000) suggested that specific haplotypes (the array of alleles on a given chromosome) may have greater predictive value regarding response to ,-agonist bronchodilators than the presence of individual polymorphisms. They reported marked variation in the ethnic distribution of the most frequently observed haplotypes (>20-fold differences) and in the mean ,-agonist responses by haplotype pair (>2-fold differences). These authors suggested that the interactions of multiple polymorphisms within a haplotype may affect biologic and therapeutic phenotype and that haplotypes may be useful as pharmacologically relevant predictive markers.

Arranz et al. (2000) recently completed a comprehensive study of variants in multiple neurotransmitters and receptors in 200 schizophrenic patients. They reported that a set of six sequence variants involving the 5-hydroxytrypta-mine (serotonin) receptor, the histamine receptor (H2) and the promoter region of the serotonin transporter gene successfully predicted response to treatment with clozapine (a neuroleptic) in 76% of patients, with a sensitivity of 95% for satisfactory response. Several of these individual polymorphisms had been previously studied in this context, but with inconsistent findings. If the results of this retrospective study are prospectively validated, then they will form the basis of a simple test to optimize the usefulness of this expensive drug in a heterogeneously responsive group of patients.

The risk of drug-induced long QT syndrome, a cause of sudden cardiac death in individuals without structural heart disease, has been linked to five gene variants, each encoding structural subunits of cardiac ion channels that affect sodium or potassium transport and are affected by anti-arrhythmics and other drugs (Priori et al., 1999). Priori et al. (1999) reported that a significant number of individuals carry "silent mutations'' of these genes; the resulting alterations are insufficient to prolong the QT interval at rest, but affected individuals may be especially sensitive to any drug that affects potassium currents. The combination of these silent mutations with even modest blockade induced by a variety of drugs used for many purposes can result in prolongation in action potential that is sufficient to trigger the onset of a serious ventricular arrhythmia (torsade de pointes).

Polymorphisms affecting steroid hormone nuclear receptors may affect individual response to drugs and hormones. For example, glucocorticoid resistance in asthma patients has been associated with increased expression of the glucocorticoid receptor ^-isoform (Sousa et al., 2000); activating mutations of the mineralocorticoid receptor have been linked to hypertension exacerbated by pregnancy (Geller et al., 2000); and dominant negative mutations of peroxisome proliferator-activated receptor gamma (PPAR gamma) have been associated with severe insulin resistance, diabetes mellitus and hypertension (Barosso et al., 1999). Huizenga et al. (1998) identified a polymorphism affecting the glucocorticoid receptor that was present in 6% of their elderly study population. These individuals appeared healthy, but exhibited increased sensitivity (reflected in cortisol suppression and insulin response) to exogenously administered glucocorticoids. The authors postulated that this increased lifelong sensitivity to endogenous glucocorticoids might be reflected in the observed trends towards increased body mass index and decreased bone mineral density in affected individuals. This polymorphism also may be related to the development of early or serious ADRs with exogenous glucocorticoid treatment in carriers, but this has not yet been established.

Some investigators have reported a relationship between variants in the angiotensin converting enzyme (ACE) gene and individual sensitivity to ACE inhibitors such as enalapril, lisinopril and captopril, but the results reported by other teams fail to show an association, so this finding remains to be confirmed (Navis et al., 1999).

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