Genetically determined polymorphisms in drug oxidation

Abstract

It is well recognized that wide interindividual variation in the efficiency of elimination can be anticipated for drugs which are predominantly eliminated by metabolism. The capacity of an individual to metabolize such a drug is dependent upon genetic and environmental factors. Numerous studies have investigated the impact of environmental factors [for reviews see (1-3)] but less information is available concerning genetic regulation. An important role for genetic factors was initially suggested by twin and family studies. Interindividual differences in drug metabolism in sibling pairs are less in identical (monozygotic) twins than in fraternal (dizygotic) twins (3). The first reports of the extent to which genetic variations contribute to interindividual variations were related to N-acetylation reactions in 1954 (4). However, it was not until 1975 that genetic polymorphisms of oxidative metabolism were reported, with the simultaneous publication of two genetic defects associated with sparteine oxidation in a German population (5) and debrisoquine hydroxylation in an English population (6). These defects were subsequently shown to be two expressions of the same gene defect. A number of other drugs have also been shown to exhibit polymorphic distribution in the efficiency of their oxidation. In some instances, defects in oxidation have been linked with debrisoquine and sparteine metabolism, in other instances, the defects in oxidation have been independent. These differences probably reflect the fact that cytochrome P-450 exists as a family of isozymes with selective but overlapping substrate and product specificity. A number of previous reviews have discussed this topic (7-10). The objective of the present review is to develop the evidence for, and pharmacokinetic and clinical consequences of, polymorphic distribution of oxidative drug metabolism. Recent advances in our understanding of the molecular basis that determines drug metabolism and its genetic regulation are presented. Finally, we have evaluated methods used in the identification of drugs that cosegregate in their metabolism.

Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients.

“…This deficiency is inherited as an autosomal recessive trait and appears to result from one of several mutations in the gene coding for a single liver cytochrome P-450 (P-4501ID gene family) (4,5). Patients with this defective cytochrome are at risk for adverse reactions to many medications (6), and may have altered risks for developing illnesses such as Parkinson's disease (7) and some cancers (1). At least eight other human liver cytochromes P-450 have now been identified (8,9).…”

Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

“…Pharmacokinetic variables affecting response to 1981), and competition for protein binding drugs include genetic factors (Jacqz et al, 1986;(Shand et al, 1975), hepatic metabolism (Shand Price Evans et al, 1960), enzyme induction etal., 1975 or renal excretion (Moller & Sheikh, (Okey et al, 1986) or inhibition (Testa & Jenner, 1983 of conjugation (e.g. N-acetylation) (Price Evans et al, 1960) or of oxidation reactions (Jacqz et al, 1986).…”

“…N-acetylation) (Price Evans et al, 1960) or of oxidation reactions (Jacqz et al, 1986). Among the latter, the ability to metabolize the antihypertensive agent debrisoquine is a useful marker of one genetically determined polymorphism (Mahgoub et al, 1977), since the disposition of over 30 other agents cosegregates with that of debrisoquine (Dayer et al, 1985;Eichelbaum et al, 1979;Kupfer et al, 1984).…”

Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.

“…0-demethylation, the limiting step in dextromethorphan metabolism and elimination, is subject to a geneticallycontrolled polymorphism related to that of debrisoquine 4-hydroxylation (Kupfer et al, 1984;Schmid et al, 1985;Larrey et al, 1987). Two phenotypes have been identified: most subjects are 'extensive metabolizers' (EM) whereas a minority of subjects, 3 to 10% of European and North American Caucasians, are 'poor Correspondence: Dr D. Larrey, INSERM U-24, H6pital Beaujon, 92118 Clichy, France. metabolizers' (PM) (Mahgoub et al, 1977;Kupfer & Preisig, 1983;Jacqz et al, 1986). The cytochrome P-450 isozyme mainly responsible for debrisoquine/dextromethorphan oxidation has been purified recently and characterized in several laboratories (Larrey et al, 1984;Gut et al, 1984;Distlerath et al, 1985).…”

“…Recent data show that the genetic deficiency in this oxidative pathway is probably caused by the complete (or almost complete) absence of this cytochrome P-450 isozyme in the liver of poor metabolizers (Gonzalez et al, 1988;Zanger et al, 1988). More than twenty drugs have been identified as being oxidized by this cytochrome P-450 isozyme including P-adrenoceptor blockers, tricyclic antidepressants, perhexiline and several antiarrhythmic agents (Kupfer & Preisig, 1983;Jacqz et al, 1986). These drugs display an oxidation polymorphism co-segregating with that of debrisoquine.…”