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. 1999 Sep;48(3):395–401. doi: 10.1046/j.1365-2125.1999.00019.x

Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population

Lise Bathum 1, Erik Skjelbo 2, Theonest K Mutabingwa 3, Hanne Madsen 1, Mogens Hørder 1, Kim Brøsen 2
PMCID: PMC2014329  PMID: 10510152

Abstract

Aims

CYP2D6 and CYP2C19 are polymorphically expressed enzymes that show marked interindividual and interethnic variation. The aim of this study was to determine the frequency of the defective alleles in CYP2D6 and CYP2C19 in Africans and to test whether the genotype for CYP2C19 is better correlated with the proguanil/cylcoguanil ratio than the mephenytoin S/R ratio.

Methods

Two hundred and sixteen black Tanzanians were phenotyped for CYP2D6 with the use of sparteine, and for CYP2C19 with the use of mephenytoin and proguanil. Of these 196 subjects were also genotyped for CYP2D6 (including the CYP2D6*1, CYP2D6*3 and CYP2D6*4 alleles) and 195 were genotyped for CYP2C19 (including the CYP2C19*1, CYP2C19*2 and the CYP2C19*3 alleles). Furthermore 100 subjects were examined for the allele duplication in CYP2D6, leading to ultrarapid metabolism, with long PCR.

Results

The sparteine metabolic ratio (MR) was statistically significantly higher in the Tanzanian group of homozygous, extensive metabolizers compared to a historical control group of white Danish extensive metabolizers. Only one poor metabolizer for CYP2D6 (MR = 124 and genotype CYP2D6*1/CYP2D6*4) was found. The gene frequencies were 0.96 for the CYP2D6*1 allele and 0.04 for the CYP2D6*4 allele. No CYP2D6*3 alleles were found. Nine subjects had an allele duplication in CYP2D6(9%). For CYP2C19 there were seven subjects (3.6%) who were phenotyped as poor metabolizers, but only three subjects (1.5%) had a genotype (CYP2C19*2/CYP2C19*2) indicative of poor metabolism. The gene frequencies were 0.90 for the CYP2C19*1 allele and 0.10 for the CYP2C19*2 allele. No CYP2C19*3 alleles were found. The mephenytoin S/R ratios were not bimodally distributed.

Conclusions

Both the genotyping and phenotyping results show that there is a substantial difference between an African black population and a Caucasian population in the capacity to metabolize drugs via CYP2D6 and CYP2C19.

Keywords: black population, CYP2C19, CYP2D6, genotype

Introduction

CYP2D6 and CYP2C19 are two polymorphic cytochrome P-450 enzymes. The extensive metabolizer (EM) phenotype occurs when there is at least one wildtype allele at the relevant gene locus. The poor metabolizer (PM) phenotype occurs when both alleles of either CYP2D6 or CYP2C19 carry inactivating mutations and give rise to synthesis of enzyme with impaired activity or no synthesis of enzyme at all.

CYP2D6 metabolizes more than 30 clinically important drugs including neuroleptics, tricyclic antidepressants, selective serotonin reuptake inhibitors, beta adrenergic drugs and opioids [1]. More than 20 inactivating mutations in the CYP2D6 gene have been reported. The nomenclature used in this article is as recommended by Daly et al. [2]. The active allele is CYP2D6*1 (formerly wt) and the most common inactive alleles are CYP2D6*4 (formerly B-mutation), CYP2D6*3 (formerly A-mutation) and CYP2D6*5 (formerly d-mutation), where the entire gene locus is deleted. The CYP2D6*4 and CYP2D6*3 alleles can be detected by allele specific PCR and this method is able to detect about 90% of the poor metabolizers in Caucasians [3]. The other extreme is a gene amplification, which gives rise to ultrarapid metabolism of drugs metabolized by CYP2D6. This duplicated allele is named CYP2D6*2 and there have been reports of up to 12 copies at the same gene locus [4].

In Caucasians approximately 8% are poor metabolizers for CYP2D6 [5] and the ultrarapid metabolizer frequency ranges from 1 to 2% in Sweden and Denmark [6, 7]–7% in Spaniards [8]. In Orientals there is a low incidence (1%) of poor metabolism [9] and there is no published data on the incidence of ultrarapid metabolism. There are several reports on the frequencies of CYP2D6 poor metabolizers in black Africans, but the results have been inconsistent. One study found an incidence of poor metabolism of 8.1% in a sample of Nigerians [10], but another study found no poor metabolizers [11]. Besides a study in Ghana showed that poor metabolizers of debrisoquine were extensive metabolizers of sparteine [12]. For both the Oriental and the African extensive metabolizer populations, a shift towards higher metabolicratios has been reported—indicating a lower CYP2D6activity compared with their Caucasian counterpart [13, 14]. In Chinese subjects this decreased activity has beenreported to be due to a C188→T substitution [15].

CYP2C19 (S-mephenytoin hydroxylase) metabolizes proguanil, omeprazole, diazepam, imipramine, citalopram, clomipramine, amitriptyline, and moclobemide [1]. In Caucasians there are approximately 3% poor metabolizers of S-mephenytoin [16]. In Orientals the frequency of poor metabolism is much higher-about 20% [9, 17]. The active allele is CYP2C19*1 (formerly wt) and the two main defective alleles in poor metabolizers are CYP2C19*2 (formerly m1) and CYP2C19*3 (formerly m2) [18, 19]. The CYP2C19*2 allele seems to be present in both Caucasians, Orientals and Africans [19–21]. The CYP2C19*3 allele is predominantly present in Orientals, and is very rare in Caucasians [21]. There are still rare inactivating mutations in CYP2C19 that remain to be sequenced.

We have previously phenotyped 216 Tanzanians for both CYP2C19 and CYP2D6 using mephenytoin, proguanil and sparteine as model drugs. The CYP2C19 phenotype data and the implications for proguanil treatment have recently been published as a separate report [22]. The aim of this study was (1) to confirm the shift towards higher metabolic ratios in Africans for both sparteine and mephenytoin reported by others (2) to determine the frequency of the defective alleles in CYP2D6 and CYP2C19 in Africans (3) to test whether the genotype for CYP2C19 is better correlated with the proguanil/cycloguanil ratio than the mephenytoin SR ratio, and (4) to determine the frequency of gene duplications in CYP2D6 in black Africans.

Methods

The study was approved by The Ethics Committee of The National Institute of Medical Research in Tanzania.

Subjects

The subjects of the study were 109 men and 107 women with a median age of 39 years. All of the subjects were black Tanzanians living in the north-eastern part of Tanzania, they were unrelated and received no medicine (except from peroral anticonception). A 10 ml blood sample was drawn from 212 of the subjects. The samples were kept in Tanzania at −20° C until all samples were collected and then sent on dry ice by air to the departments of Clinical Pharmacology and Clinical Biochemistry in Odense, where the laboratory analysis was performed.

Phenotyping

Each subject took 100 mg racemic mephenytoin (Mesantoin, Sandoz Pharmaceuticals, East Hannover, New Jersey, USA) and 100 mg sparteine sulphate (Depasan, Guilini Pharma GmbH, Hannover, Germany), followed by urine collection for 8 h. One week later all subjects took a single oral dose of 200 mg chloroguanide hydrochloride (Paludrine®, ICI Pharmaceuticals, Macclesfield, England), and urine was collected for 8 h. Urine volumes were immediately recorded, and an aliquot was kept frozen at −20° C for less than 4 months. The urine samples were then transported on dry ice by air to Denmark, where the samples were assayed within 1 month. Sparteine, 2,3-didehydrosparteine and 5,6-didehydrosparteine were assayed by gas chromatography [23]. A metabolic ratio (MR) was calculated as sparteine/(2,3-plus 5,6-didehydrosparteine). Extensive metabolizers were defined as subjects with a MR less than 20 and the poor metabolizers with a MR above 20.

Mephenytoin is a racemic drug, and unchanged S- and R-mephenytoin in urine was assayed by gas chromatography [24]. The S/R mephenytoin ratio was calculated as the ratio between the chromatographic peak areas of S- and R-mephenytoin. Chloroguanide hydrochloride and cycloguanil were assayed by an h.p.l.c. method as described earlier [22].

Isolation of DNA

The DNA was isolated with a standard enzymatic method using pronase. Probably due to episodes of melting and freezing caused by electric breakdown during the storage in Tanzania, it was only possible to isolate DNA from 131 blood samples in the first shipment. Additionally 66 blood samples were recollected and in total DNA was isolated from 197 samples.

Genotyping for CYP2D6

The genotyping procedure was performed by allele specific PCR and carried out according to Heim and Meyer [25]. This procedure identifies the alleles CYP2D6*1, CYP2D6*3 and CYP2D6*4.Genotyping for CYP2D6 was possible in 196 subjects. Because of the poor condition of the DNA, it was not possible to examine for the CYP2D6*5 allele neither by RFLP nor by long PCR.

Analysis for the amplification of CYP2D6 by long PCR

The analysis for the duplicated alleles for CYP2D6 was carried out as described by Løvlie et al. [26]. The following primers were used (forward) 5′-TCCCCCACTGACCCAACTCT-3′ and (reverse) 5′-CACGTGCAGGGCACCTAGAT-3′. This primer combination amplifies a 5.2-kb PCR fragment from the CYP2D7-CYP2D6 intergenic region and in addition a 3.6-kb PCR fragment is amplified from the CYP2D6-CYP2D6 region in subjects with an amplification. It was only possible to examine 100 subjects with this long PCR. The remainder showed no amplification because of fragmented DNA.

Genotyping for CYP2C19

The genotyping for CYP2C19 identified the alleles CYP2C19*1, CYP2C19*2 and CYP2C19*3. The first step is a PCR as described by de Morais et al. [18, 19]. For amplification of the CYP2C19*2 allele, primers flanking intron 4 and exon 5 were used. For amplification of the CYP2C19*3 allele, primers flanking exon 4 were used. The mutation detection was performed with an oligonucleotide ligation assay developed in our laboratory [27].

Control group

The phenotyping data for CYP2D6 is compared with the data from a group of 323 healthy Danish subjects. They were pheno-and genotyped for CYP2D6 in a population study examining the imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms [28].

Statistics

The allele frequencies were computed by counting genes from the observed genotypes. The relation between genotype and phenotype are reported as medians and 95% confidence intervals. The statistical analysis was carried out by means of the MEDSTAT computer program package, version 2.12 (Astra group, Albertslund, Denmark). Only subjects in whom a genotype for CYP2D6 and CYP2C19 were established, were included in the statistical analysis. The comparison between homozygous and heterozygous Tanzanians and between the Tanzanians and the historical Danish control group for CYP2D6, was done with the two sample rank sum test (Mann–Whitney).

Results

It was possible to genotype 196 Tanzanians. No sparteine or metabolites were detected in one subject—genotyped as CYP2D6*1/CYP2D6*4—who probably did not take the drug. The distribution of the sparteine MR in 195 geno-and phenotyped Tanzanians is shown in Figure 1. Thus the MR ranged from 0.06 to 9.8 in 194 extensive metabolizers and it was 124 in one poor metabolizer subject. The poor metabolizer was genotyped as CYP2D6*1/CYP2D6*4, and among the extensive metabolizers there were 182 homozygous CYP2D6*1/CYP2D6*1 (or CYP2D6*1/CYP2D6*5) and 12 heterozygous CYP2D6*1/CYP2D6*4. No CYP2D6*3 alleles were detected. Accordingly the frequency of the CYP2D6*1 allele and (95% confidence intervals) were 0.96 (0.94–0.98) and of the CYP2D6*4 allele 0.04 (0.02–0.06).

Figure 1.

Figure 1

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Phenotyping data for CYP2D6 in Tanzanians. *1/*4+a–CYP2D6*1/CYP2D6*4 with a duplication (Inline graphic), *1/*4–CYP2D6*1/CYP2D6*4 (Inline graphic), *1/*1+a–CYP2D6*1/CYP2D6*1 with a duplication (▪) and *1/*1–CYP2D6*1/CYP2D6*1 (□). All subjects were both pheno-and genotyped, but only 100 subjects could be examined for the duplication in CYP2D6 with long PCR.

The median and (95% confidence interval) of the MR in the 182 apparently homozygous, extensive metabolizers CYP2D6*1/CYP2D6*1 was 0.67 (0.14–3.80) as compared to 0.32 (0.28–0.35) in a historical control group comprising 198 Danes with the same genotype [28]. The similar values in 12 heterozygous, extensive metabolizers CYP2D6*1/CYP2D6*4 Tanzanians and a historical control group of 100 Danish extensive metabolizers [28] (8 CYP2D6*1/CYP2D6*3 and92 CYP2D6*1/CYP2D6*4) were 0.63 (0.35–1.68) and 0.57 (0.49–0.65), respectively. The z-value calculated from the Mann–Whitney test for comparison of the two homozygous ethnic groups are −7.95 (P < 0.0001) and the corresponding difference for the two heterozygous groups is −0.76 (P = 0.45). Among the Tanzanians, the z-value for comparison of the homozygous and heterozygous extensive metabolizers are—0.62 (P = 0.54). Thus there is a significant difference between the distribution of metabolic ratios in the homozygous Tanzanian and Caucasian extensive metabolizers, but not between the heterozygous Tanzanian and Caucasian extensive metabolizers or between the homozygous and heterozygous Tanzanians.

DNA of sufficient quality for assay by long PCR was obtained from 100 individuals. In nine subjects a duplicated CYP2D6 allele was detected and their MR ranged from 0.08 to 1.31 with a median of 0.59. Eight of the 12 heterozygous, extensive metabolizers CYP2D6*1/CYP2D6*4 could be tested with long PCR and in four of these a duplicated allele was seen.

The mephenytoin and proguanil phenotyping data has previously been published [22]. CYP2C19 genotyping was carried out in 195 of the Tanzanians. There were 160 homozygous CYP2C19*1/CYP2C19*1, 32 heterozygous CYP2C19*1/CYP2C19*2 and three homozygous CYP2C19*2/CYP2C19*2. One extensive metabolizer showed no signal in the CYP2C19 genotyping and was excluded. The CYPC19*3 mutation was not detected in any of the subjects. Overall the frequencies and (95% confidence intervals) of CYP2C19*1 and CYP2C19*2 were 0.90 (0.87–0.93) and 0.10 (0.07–0.13). The cutoff between poor and extensive metabolizers is in European populations set to an S/R for mephenytoin at 0.9. But in this Tanzanian population the phenotypically poor and extensive metabolizers were not clearly separated by the mephenytoin S/R. The distribution of mephenytoin S/R was not bimodal and there were seven subjects with a mephenytoin S/R above 0.9, but only three of these were also genotyped as poor metabolizers and four were homozygous CYP2C19*1/CYP2C19*1 and are therefore in the following considered as extensive metabolizers. These four subjects had high proguanil/cycloguanil ratios as well (12, 63, 249 and 12). The results for CYP2C19 are shown in Table 1 and Figure 2. The two CYP2C19 phenotype indices in the three genotypes are summarized in Table 1. Thus each of the two urinary ratios were much higher in the three genotypically poor metabolizers than in the two extensive metabolizer genotype groups and statistically significantly higher in the CYP2C19*1/CYP2C19*2 than in the CYP2C19*1/CYP2C19*1.

Table 1.

The CYP2C19 phenotype* and genotype data in 195 Tanzanians.

graphic file with name bcp0048-0395-t1.jpg

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Figure 2.

Figure 2

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Relation between genotype for CYP2C19 and (a) the mephenytoin S/R ratio and (b) the proguanil/cycloguanil ratio. Empty boxes are homozygous CYP2C19*1/CYP2C19*1, hatched are heterozygous CYP2C19*1/CYP2C19*2and solid are homozygous CYP2C19*2/CYP2C19*2.

Discussion

The phenotyping data for sparteine showed a shift towards higher metabolic ratios in the Tanzanians compared to a Caucasian group. The median for MR for sparteine was higher in Tanzanians for both homozygous and heterozygous subjects and this difference is statistically significant between the homozygous CYP2D6*1/CYP2D6*1 groups, but not between the heterozygous CYP2D6*1/CYP2D6*4 groups. The median for MR for sparteine in the Tanzanians was lower in the heterozygous group than in the homozygous group. This indicates that the inactive allele CYP2D6*4 is not essential in determining the MR in Tanzanians in contrast to Caucasians [8] and there must be other factors more important such as heterogeneity in CYP2D6*1 or inhibitory substances in the environment. In this study we did not examine for the CYP2D6*5 allele. This allele can be present in homozygotes but not in heterozygotes. The frequency of this allele has been reported to be 5% in the European population [29] and 3.9% in Zimbabwe [30]. A very high frequency of this allele could explain the higher metabolic ratios in the Tanzanian population, but is not likely because of the low frequency of poor metabolizers.

Two recent studies examined the CYP2D6 genelocus in Africans. One earlier study genotyped 114 Zimbabweans and found a very low frequency of defective alleles and no subjects with a genotype indicative for the poor metabolizer phenotype (the subjects were apparently not phenotyped) [30]. One study—also in black Zimbabweans [31]—found a new allele denoted CYP2D6*17 with 3 base changes; C1111-T, C2938-T and G4268-C. This allele was found with an allele frequency of 34% and was strongly associated with a lower capacity for debrisoquine hydroxylation. We did not examine for this allele in our Tanzanian population, but it might be the reason for the shift towards higher metabolic ratios. At the other extreme one recent study showed a frequency of 29% of ultrarapid metabolizers in a black Ethiopian population [32].

In the present study we found only one subject who was phenotyped to be a poor metabolizer for CYP2D6 and the genotyping revealed the heterozygous genotype CYP2D6*1/CYP2D6*4. This indicates that the frequency of poor metabolism in the Tanzanian population is very low and supports the low prevalence of the poor metabolism seen in other black populations [30, 33, 34]. This also indicates that there must be other inactivating mutations than CYP2D6*3and CYP2D6*4 in this population. No CYP2D6*3 alleles and only very few CYP2D6*4alleles were found. This is in accordance with the earlier study made in Zimbaweans [30]. The right shift in the phenotyping data is obviously not because of a higher frequency of the inactivating alleles CYP2D6*3 and CYP2D6*4 compared to Caucasians.

The phenotyping data for mephenytoin showed no evidence of a bimodal distribution (Figure 2). The relation between mephenytoin S/R, the ratio proguanil/cycloguanil and genotype is shown in Table 1 and Figure 2. There is a significant difference between the homozygous CYP2C19*1/CYP2C19*1 and the heterozygous CYP2C19*1/CYP2C19*2 groups for the two urinary ratios (Table 1). There is no clear difference in the separation of genotypes between mephenytoin S/R and the ratio proguanil/cycloguanil. The genotype CYP2C19*2/CYP2C19*2 is clearly separated from the genotypes CYP2C19*1/CYP2C19*1 and CYP2C19*1/CYP2C19*2 in both cases.

In two similar studies using genotype techniques in black Ethiopians and black Zimbabweans, the poor metabolizer frequency was 5.2% [35] and 4% [20]. In this study we found no CYP2C19*3 alleles, but the gene frequencies for CYP2C19*1 and CYP2C19*2 were the same as in earlier genotyping studies among black Ethiopians [35] and black Zimbabweans [20]. The frequency of subjects with a genotype indicative of poor metabolism is a bit lower than in the Caucasian population and in earlier genotyped African populations. Also, there were four subjects with a genotype indicative of extensive metabolism with an S/R for mephenytoin at the same level as the three subjects with a genotype indicative of poor metabolism. This could mean that there are still unknown mutations in CYP2C19 or that the mephenytoin S/R ratios are artificially raised. The blood and urine were frozen shortly after collection and send on dry ice to Denmark. But there were many episodes of melting and freezing in Tanzania and several blood samples had to be recollected. This treatment could affect mephenytoin and thereby alter the S/R. The S/R mephenytoin ratio could change due to conversion of an acid labile metabolite of mephenytoin to S-mephenytoin [36]. The poor metabolizers do not produce this metabolite, but some extensive metabolizers do. This could artificially raise their S/R ratio and lead to an overestimation of the poor metabolizer phenotype. We believe that this could be the reason for the apparently higher S/R ratios and lack of bimodality. The golden standard as a probe for phenotyping for CYP2C19 is mephenytoin, but when samples are collected under difficult conditions, mephenytoin is not ideal. We would consider using another probe drug such as omeprazole [37] for future studies under these conditions. The four subjects with an S/R ratio above 0.9 and the genotype CYP2C19*1/CYP2C19*1 all had very high proguanil/cycloguanil ratios. This probably means that there are still unknown mutations in CYP2C19 and that these four subjects were true poor metabolizers.

The long PCR assay for the duplication in CYP2D6 revealed 9 duplicated alleles in 100 subjects. Four of the duplications were found in subjects with the genotype CYP2D6*1/CYP2D6*4 out of 8 subjects tested with long PCR in this genotype. This is far more than expected. The 42 kb allele seen in XbaI RFLP (restriction fragment length polymorphism) is usually indicative of a duplication of the functional CYP2D6 gene and this allele gives the amplification seen in different methods involving long PCR [26, 38]. However, two earlier studies—one in black Americans and one in Zimbaweans revealed a 42-kb allele with duplicated, but nonfunctional CYP2D6 genes [26, 30]. In total there is 9% of this subgroup that carries a duplicated allele. But as seen on the phenotyping data (Figure 1) it is not possible to distinguish a group of ultrarapid metabolizers.

We conclude that both the genotyping and the phenotyping results show that there is a substantial difference between an African black population and a Caucasian population in the capacity to metabolize drugs via CYP2D6 and CYP2C19.

Acknowledgments

The valuable technical assistance of Mrs Dorte Jensen is highly appreciated. We are indebted to the community leadership in the six communities of Muheza for allowing us to perform the study. The services of Mr L. N. Malle in the collection and processing of urine specimens in Tanzania is highly appreciated. This study was supported from the Danish Ministry for Foreign affairs, Copenhagen (grant 104.Dan. (/616) and the Danish Medical Research Council, Copenhagen (grant 12–1654–1 and grant 9400464).

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