Genetic polymorphism of drug metabolizing enzymes in the Shona and the San in Zimbabwe and the clinical impact of CYP2D6 polymorphism on safety in the use of psychotropics

Abstract

INTRODUCTION: Interindividual variability to drug response is a well known

phenomenon and dates back to the 1950s with isoniazid. When the same dose of the same

drug is given to different individuals, some may respond well, while others may respond but

with side effects, whilst others may not even respond at all. In a number of instances, this

variability has been shown to be due to genetic differences. The best documented are

pharmacokinetic differences due to polymorphism of drug metabolising enzymes, in

particular CYP2D6 which metabolises about 25% of clinically used drugs. The frequencies

of these mutations have been studied to a great extent in Caucasians and Orientals, and some

have shown to be variable among different ethnic groups. Africans have also been studied

but to a much lesser extent, yet they may be even more diverse. We sought to investigate the

frequencies of mutations of some drug metabolising enzymes in Zimbabwean ethnic groups

and the impact of CYP2D6 polymorphism in psychiatric patients on routine drug therapy in a

naturalistic setting.

MATERIALS AND METHODS: The study was approved by the Medical Research

Council of Zimbabwe and the volunteers gave written informed consent. Seventy-eight

Shona volunteers were recruited from the University of Zimbabwe Medical School whilst 63

San volunteers were recruited from the Plumtree district in Zimbabwe. Fifty psychiatric

patients were interviewed at the Parirenyatwa Hospital Psychiatric unit. Five mL blood

samples were drawn from all volunteers and stored at minus 20 °C until required for

genotyping. An additional 5 mL blood sample was drawn from each of the psychiatric

patients and the plasma was stored at minus 20 °C until required for analysis. PCR-RFLP

methods were used to genotype for CYP2C19*2, CYP2B6*6, CYP2D6*4, *17 and *29

mutations. LC-MS was used for the measurement of plasma concentrations of

chlorpromazine, thioridazine, fluphenazine, haloperidol, amitriptyline and nortriptyline.

Drug plasma levels were then correlated against CYP2D6 genotype.

RESULTS: Frequencies for CYP2C19*2, CYP2B6*6, CYP2D6*4, *17 and *29 in the Shona

were 0.16, 0.38, 0.05, 0.22, and 0.16, whilst in the San they were 0.12, 0.40, 0.10, 0.22 and

0.02 respectively. Differences between drug concentrations stratified by CYP2D6 genotype

were observed for thioridazine versus CYP2D6*29 and for fluphenazine versus CYP2D6*17

genotypes. No significant correlations were found for the other drugs.

DISCUSSION: Genetic polymorphism of the drug metabolising enzymes CYP2B6,

CYP2C19 and CYP2D6 was similar between the San and the Shona, except for the frequency

of, CYP2D6*29, an African-specific mutation, which was virtually absent in the San. The

most prevalent mutation in both populations was CYP2B6*6, which has implications for a

lower population-specific dose of the antiretroviral drug efavirenz to avoid central nervous

system side effects. Carriers of CYP2D6*29 and CYP2D6*17 mutations need lower doses of

thioridazine and fluphenazine respectively to avoid side effects related to high drug plasma

levels.

CONCLUSION: We investigated frequencies of mutations of the following drug

metabolizing enzyme genes; CP2D6, CYP2C19 and CYP2B6 in the Shona and the San.

Although clear relationships between CYP2D6 genotype and thioridazine and fluphenazine

concentrations were observed, these did not reach statistical significance due to the limited

sample.size.