Polymorphisms Affecting Drug Metabolism

Most drugs are degraded via a limited number of metabolic pathways, most of which involve microsomal hepatic enzymes. Ingelman-Sundberg et al. (1999) reported that about 40% of this human cytochrome (CYP) P450-dependent drug metabolism is carried out by polymorphic enzymes capable of altering these metabolic pathways. The CYP P450 monooxygenase system of enzymes detoxifies xenobiotics and activates procarcino-gens and promutagens in the body via oxidative metabolic pathways. These enzymes play an important role in the elimination of endogenous substrates (such as cholesterol) and lipophilic compounds (such as central nervous system (CNS) drugs that cross the blood-brain barrier), which otherwise tend to accumulate to toxic concentrations. This very large and well-studied gene family consists of many isoforms; for example, over 70 variant alleles of the CYP2D6 locus have been described (Ingelman-Sundberg et al., 1999). The distribution of variant alleles for these enzymes differs among ethnic and racial subpopulations, with significant implications for clinical practice in various areas (Table 43.1). Alleles causing altered (enhanced or diminished) rates of drug metabolism have been described for many of the P450 enzymes, and the underlying molecular mechanisms have been identified for some. Table 43.2 summarizes some clinically significant polymorphisms affecting drug metabolism and the drugs and drug effects associated with them; a comprehensive summary is available at <http://www.sciencemag.org/ feature/data/1044449.shl>. Continuously updated descriptions of these alleles and accompanying references can be found at <http:// www.imm.ki.se/CYPalleles/>

CYP2D6, which encodes debrisoquin hydroxy-lase, was the first of these enzyme-coding genes to be cloned and characterized, and it remains among the most studied. It is involved in the metabolism of many commonly used drugs, including tricyclic anti-depressants, neuroleptics, anti-arrhythmics and other cardiovascular drugs, and opioids. Variant alleles may differ from the wild-type (normal) gene by one or more point mutations, gene deletions, duplications, multiduplications or amplification. These may have no effect on enzyme activity or may code for an enzyme with reduced, absent or increased activity. The genetics and related biochemistry of these pathways are still being elucidated and are more complex than the following simplistic descriptions imply. Extensive metaboli-zers, 75%-85% of the general population, are homozygous or heterozygous for the wild-type, normal activity enzyme. Intermediate (10-15% of the population) and poor (5%-10%) metabolizers carry two reduced or loss-of-activity alleles. These individuals are likely to exhibit increased drug plasma concentrations when given standard doses of drugs that are metabolized by this enzyme; this

Table 43.1. Population distribution of selected polymorphic drug-metabolizing enzymes.3

Allelle frequency (%)

Major Functional Black Ethiopian and

Enzyme polymorphisms consequences Caucasian Asian African Saudi Arabian

Major Functional Black Ethiopian and

Enzyme polymorphisms consequences Caucasian Asian African Saudi Arabian

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