Genetic Polymorphism of Drug Metabolising Enzymes in African Populations: Implications for the Use of Neuroleptics and Antidepressants

Abstract

Metabolism of most drugs influences their pharmacological and toxicological effects. Drugs particularly affected are those with a narrow therapeutic window and that are subjected to considerable first-pass metabolism. Much of the interindividual and interethnic differences in effects of drugs is now attributable to genetic differences in their metabolism. Genetic polymorphisms have been described for many drug-metabolising enzymes in Caucasian and Oriental populations, the most well-characterised being those for cytochrome P450 2D6, cytochrome P450 2C19, glutathione S-transferases, and N-acetyl transferase 2. African populations have been studied to a lesser extent, but it is apparent that populations within Africa are heterogeneous with respect to these polymorphisms. In addition, although some allelic variants are common to all populations throughout the world (e.g., CYP2D6∗5), some allelic variants are specific for an African population (e.g., CYP2D6∗17). The polymorphisms give rise to enzymes with changed or no activity towards drug substrates. Two of the most important enzymes for metabolism of neuroleptics and other psychoactive drugs are CYP2D6 and CYP2C19. This article compares the current information on polymorphisms of these two enzymes in African and other populations and discusses the implications of these polymorphisms for neuropharmacotherapy.

Introduction

Drugs acting on the central nervous system show great interindividual and interethnic variation in effect. Factors responsible for this variability range from extent of drug-protein binding, metabolism to active and inactive metabolites, and variability in amount or sensitivity of drug-target receptor. Metabolism is a major determinant of the pharmacological and toxicological effects of the administered drug. Most psychotropic drugs, like other drugs, are lipophilic, which enables them to cross membrane barriers to reach their target receptors. Metabolism to more water-soluble products is necessary for their elimination, and failure to do so can lead to drug accumulation, which is associated with the intensification of adverse effects, some of which can be fatal. The major enzyme systems involved in the biotransformation of drugs are cytochromes P450 (CYP), glutathione S-transferases (GST), UDP-glucuronosyl transferases, sulfanotransferases, and N-acetyltransferases (NAT), which are mainly found in the liver, although they are also present in other tissues at lower levels. Environmental and genetic factors affect the activities of these enzymes, which can lead to enhanced or decreased drug biotransformation and disposition.

Considerable international interest, shown by the growth of the field of pharmacogenetics, has focused in the past 10–20 years on genetic factors affecting the efficacy of drugs. Mutations in a gene coding for a drug metabolising enzyme can give rise to enzyme variants with higher, lower, or no activity. If the mutant allele occurs with a frequency of at least 1–2% in the normal population and causes a different drug response or phenotype, this phenomenon is termed a pharmacogenetic polymorphism. Polymorphisms of drug metabolism divide the population into at least two phenotypes, extensive and poor metabolisers [54]. Polymorphisms have been detected in many drug-metabolising enzymes at both the genotypic and phenotypic level. Two of the most well-studied and best-characterised polymorphisms are those for debrisoquine 4-hydroxylase (cytochrome P450 2D6) [28] and S-mephenytoin hydroxylase (cytochrome P4502 C19) [24]. Studies comparing the status of these enzymes in Caucasians and Orientals have clearly demonstrated interethnic genetic differences, which produce clinically important population differences in response to many drugs 7, 44. Cytochrome P4502D6 (CYP2D6) has been shown to metabolise most of the neuroleptics and antidepressants currently in use (Table 1), while cytochrome P4502C19 (CYP2C19) has been shown to metabolise diazepam 4, 7. A number of reviews have been published on genetic variation of cytochrome P450 activity and its implications for neuropharmacotherapy in Caucasoid (Europeans and white North Americans) and Oriental (Chinese, Japanese, and Koreans) populations 7, 43, 71, 77. No review has focused on African populations, however, and we therefore address this issue here by reviewing the status of these enzymes in different populations and discuss possible implications for the use of neuroleptics and antidepressants in African populations.