Chapter 9

## Abstract

Abstract

1. Pharmacogenetics has been defined as the science that deals with pharmacologic responses and their modification by hereditary influences. Much clinical work has been done under this broad label. Variation of drug-metabolizing enzymes, responsible for a large section of pharmacogenetics, represents person-to-person differences within the chemical defense systems. These differences and the variations that affect susceptibility to infectious diseases (e.g., tuberculosis and malaria) may have comparable biologic effects: They will aid the survival of populations exposed to toxins or to infectious agents, respectively.

2. The history and scope of pharmacogenetics have been outlined briefly. Various chapters in this book might have been classified by their contents as part of pharmacogenetics [e.g., glucose-6-phosphate dehydrogenase (G-6-PD) deficiency] but they are treated as independent entities and presented on their own merits. This chapter on pharmacogenetics presents three selected case studies that are of unquestioned clinical importance and, at the same time, illustrate a wide range of problems.

3. Malignant hyperthermia (MH) is the most feared complication of general anesthesia, observed in about 1:15,000 children and 1:100,000 adults; it occurs on the basis of genetic predisposition affecting skeletal muscle. It is not a uniform disease, but its common parameter is pathologic elevation of ionized calcium in the sarcoplasm. This calcium triggers muscle rigidity, elevation of body temperature, acidosis, tachycardia, and other secondary events. Clinically, an MH attack is most frequently triggered by halothane and succinylcholine; for diagnostic purposes, contractures of muscle biopsy specimens on exposure to caffeine and/or halothane are utilized. An equivalent abnormality in pigs is caused by a Cys for Arg615 substitution in the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum. Predisposition to MH in humans is often but not always caused by the same mutation.

4. In the 1950s, a variant (atypical) form of butyrylcholinesterase (BChE) was found to be responsible for the prolongation of action of the muscle relaxant succinylcholine. Any physiological function of BChE is still not known, but it is known to be a homotetramer produced by a single gene on chromosome 3 at q26.1-26.2. Mutations with an allele frequency of 0.017 in Caucasians may affect its capacities for substrate binding, its turnover numbers, or both combined in linkage disequilibrium; some silent variants are inactive, and some represent frameshift mutations with absence of enzyme protein. Originally, the clinical interest in BChE deficiency centered on the prolonged action of the normally short-acting succinylcholine when given during anesthesia. Of recent interest is the metabolism of cocaine by BChE; infusions of purified BChE promise to relieve cocaine toxicity, particularly when the drug has been applied in multiple doses or in forms designed for rapid absorption. Recent areas of study are questions of a role of BChE in Alzheimer disease, or of BChE variants as contributors to the Gulf War syndromes because of abnormalities of pyridostigmine action.

5. A genetic polymorphism now known to affect the oxidative biotransformation of debrisoquine, sparteine, and over 60 other therapeutic agents was first described in the mid-1970s. This genetic defect affects the function of a specific isozyme of cytochrome P450, namely, CYP2D6, and it has been intensively investigated with respect to both its clinical and toxicologic implications and its underlying biochemical and molecular mechanisms. The CYP2D gene cluster, located on chromosome 22q13.1, is highly polymorphic in the human population. It may contain from two to four genes, only one of which (CYP2D6) produces functional enzyme in individuals of the extensive metabolizer (EM) phenotype. Poor metabolizers (PMs) of debrisoquine possess two of the almost 60 known mutant CYP2D6 alleles. Of these, the four most common mutants account for about 90 percent of defective alleles in Caucasian populations and lead to impairment in expression of functional CYP2D6 protein by mechanisms ranging from deletion of the entire gene to single nucleotide substitutions that lead to premature translation termination. The clinical importance of genetically variable CYP2D6 function for the response to a given drug or other foreign chemical will depend on the quantitative significance of CYP2D6 in governing the compound's fate, its therapeutic window, the extent of its use in clinical practice, and the availability of therapeutic alternatives.

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