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Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in Aborigines from Western Australia

Griese, Ernst-Ulricha; Ilett, Kenneth F.b,c; Kitteringham, Neil R.d; Eichelbaum, Michela; Powell, Helend; Spargo, Randolph M.e; LeSouef, Peter N.f; Musk, A. Williamg; Minchin, Rodney F.b,h

Original Article
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The polymorphisms of the important xenobiotic metabolizing enzymes CYP2D6, CYP2C19 and CYP2E1 have been studied extensively in a large number of populations and show significant heterogeneity in the frequency of different alleles/genotypes and in the prevalence of the extensive and poor metabolizer phenotypes. Understanding of inter-ethnic differences in genotypes is important in prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics. Since no data were available for Australian Aborigines, we investigated the frequencies of alleles and genotypes for CYP2D6, CYP2C19 and CYP2E1 in a population living in the far north of Western Australia. Because of its geographical isolation, this population can serve as a model to study the impact of evolutionary forces on the distribution of different alleles for xenobiotic metabolizing enzymes. Twelve CYP2D6 alleles were analysed. The wild-type allele *1 was the most frequent (85.8%) and the non-functional alleles (*4, *5, *16) had an overall frequency of less than 10%. Only one subject (0.4%) was a poor metabolizer for CYP2D6 because of the genotype *5/*5. For CYP2C19, the frequencies of the *1 (wild-type) and the non-functional (*2 and *3) alleles were 50.2%, 35.5% and 14.3%, respectively. The combined CYP2C19 genotypes (*2/*2, *2/*3 or *3/*3) correspond to a predicted frequency of 25.6% for the CYP2C19 poor metabolizer phenotype. For CYP2E1, only one subject had the rare c2 allele giving an overall allele frequency of 0.2%. For CYP2D6 and CYP2C19, allele frequencies and predicted phenotypes differed significantly from those for Caucasians but were similar to those for Orientals indicating a close relationship to East Asian populations. Differences between Aborigines and Orientals in allele frequencies for CYP2D6 *10 and CYP2E1 c2 may have arisen through natural selection, or genetic drift, respectively.

aDr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, bDepartment of Pharmacology, University of Western Australia, Nedlands, Western Australia, cClinical Pharmacology and Toxicology Laboratory, The Western Australian Centre for Pathology and Medical Research, Nedlands, Western Australia, dDepartment of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK, ePuntkurnu Aboriginal Medical Service, Jigalong Clinic via Newman, Western Australia, fDepartment of Paediatrics, University of Western Australia, Nedlands, Western Australia, gDepartment of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia and hLaboratory for Cancer Medicine, Royal Perth Hospital, Perth, Western Australia

Received 20 January 2000; accepted 5 July 2000

Correspondence to K.F. Ilett, Department of Pharmacology, University of Western Australia, Nedlands, 6907, Western Australia E-mail: kilett@receptor.pharm.uwa.edu.au

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Introduction

Cytochrome P450 enzymes (CYP) play a central role in the metabolism of many drugs, chemicals and carcinogens. Differences in the activity of these enzymes are being held responsible for the interindividual variability in drug response and toxicity as well as susceptibility towards chemical induced carcinogenesis. Among the CYP enzymes the isoforms, 2C19, 2D6 and 2E1 are of particular interest because they exhibit a genetic polymorphism. In the case of 2D6 and 2C19, carriers of two nonfunctional alleles have a severe impaired capacity to metabolize drugs that are substrates for these enzymes and hence are designated as poor metabolizers.

For CYP2D6, more than 50 drugs, including anti-arrhythmics, antidepressants, β-adrenoceptor antagonists, neuroleptics and opioids have been identified as substrates of this enzyme. Poor metabolizers have a much higher risk of developing concentration-related side-effects and toxicity (Eichelbaum & Gross, 1990). At the other extreme, therapeutic failure with substrates such as the tricyclic antidepressant nortriptyline is attributable to the occurrence of CYP2D6 gene amplification resulting in the ultrarapid metabolizer phenotype (Bertilsson et al., 1993;Dalen et al., 1998). On the other hand, if therapeutic effect is not mediated by the parent drug but a metabolite, loss of efficacy will be observed in poor metabolizers as it has been demonstrated for codeine (Mikus et al., 1994) and tramadol (Poulsen et al., 1996). CYP2C19 metabolizes clinically important drugs such as mephenytoin, propranolol, omeprazole, imipramine, diazepam, citalopram and proguanil (Brøsen, 1996;Goldstein et al., 1997) and also phenytoin to a lesser extent (Levy, 1995). Human CYP2E1 is involved in the oxidation of drugs such as ethanol, chlorzoxazone, acetaminophen and fluorinated anaesthetics (Raucy et al., 1993;Dupont et al., 1998) as well as in metabolic activation of a variety of carcinogens (Guengerich et al., 1991). It can be induced by ethanol, and studies have shown an approximate 50-fold interindividual variability in its expression (Umeno et al., 1988;Kim & O'Shea, 1995). In addition, the c2 mutant allele in the regulatory 5′-flanking region has been associated with higher transcriptional activity (Hayashi et al., 1991;Tsutsumi et al., 1994b;Watanabe et al., 1994).

For CYP2D6 and CYP2C19, the prevalence of loss of functional alleles or of alleles encoding for enzymes with impaired activity varies substantially in populations of different racial origin. Furthermore, some alleles have been found only in certain racial/ethnic groups, as is the case for CYP2D6*17 in Black Africans (Masimirembwa et al., 1996).

While the frequency of mutant alleles of 2D6 and 2C19 has been studied in all major human races, no data are available for Australian Aborigines. The Aborigines are considered to be separate from the main Caucasoid, Mongoloid and Negroid races (Bertilsson, 1995). Moreover, because the Aborigines appeared on the Australian continent approximately 30–60 000 years ago (Sergeantson & Hill, 1989;Flannery, 1994;Bertilsson, 1995), they will have had only very limited contact with other population groups. Therefore, gene frequencies in the Aborigine should be less disturbed by factors such as migration, and more influenced by natural selection and new mutations. Indeed, we have previously reported a unique distribution of N-acetyltransferase 2 (Ilett et al., 1993) and glutathione S-transferase alleles (Ilett et al., 2000) in Aborigines from the far north of Western Australia. In view of the importance of the CYP enzymes in the biotransformation of xenobiotics, we have investigated the frequencies of the CYP2D6, CYP2C19 and CYP2E1 genotypes in an Australian Aborigine population from the far north of Western Australia. Our data show that the Australian Aborigine is similar to Oriental populations for CYP2D6 (except *10) and CYP2C19 but differs with regard to CYP2E1.

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Subjects and methods

Subjects

A population of 239 individuals (124 females, 115 males) from an Aboriginal Community, in a remote area of the far north of Western Australia was studied as part of an ongoing larger investigation of health in this Community. The total population of the Community varies seasonally but is estimated to be 300–350 persons. The data in this study are derived from samples collected during the 1995 Health Survey. The study protocol was approved by the Human Rights Committee of the University of Western Australia and written informed consent was obtained from all participants. The population studied is geographically isolated and only three different maternal language groups are represented.

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Genotyping

Blood was obtained by venepuncture and anticoagulated with EDTA. After centrifugation (1500 g for 15 min), the buffy coat was removed, digested at 37 °C with a proteinase K-containing buffer, and genomic DNA was extracted by use of the phenol-chloroform method (Sambrook et al., 1989). Polymerase chain reaction (PCR) assays, with or without restriction fragment length polymorphism were used to examine the polymorphisms for CYP2D6, CYP2C19 and CYP2E1.

Twelve CYP2D6 alleles, among them five functional (*1, *2, *2xN, *10, *17) and seven non-functional alleles (*3, *4, *5, *6, *7, *8, *16), were analysed by an allele-specific multiplex PCR (*3, *4, *6, *7, *8), allele-specific long distance PCR (*5, *16, *2xN) or conventional allele-specific PCR assays (*2, *10, *17) (Stuven et al., 1996;Griese et al., 1998). Functional (*1; wild-type) and non-functional (*2, *3) alleles for CYP2C19 were identified by allele-specific PCR in a multiplex format (Griese et al., 1999a) in a subgroup of 227 individuals. For CYP2E1, the Rsa1-polymorphism in the 5′-flanking region of the gene was investigated in 237 individuals by the method of Hayashi et al. (1991) with minor modifications (Pirmohamed et al., 1995). In addition, the presence or absence of the Rsa I-linked Pst I mutation (Watanabe et al., 1990) also was confirmed using the same primers and DNA from 17% of the subjects selected at random.

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Results

CYP2D6 genotyping

Genotyping for 12 CYP2D6 alleles (Table 1) was carried out in all 239 subjects. The wild-type allele *1 had by far the highest frequency (85.8%) and all other functional alleles (*2, *10, *17) had frequencies equal to or less than 3.8%, respectively. Of the seven known non-functional CYP2D6 alleles only *4, *5 and *16 were found. Allele *5 was more frequent (7.5%) than the other null alleles *4 (1.5%) and *16 (0.4%). There was no incidence of amplified *2 alleles (allele *2xN).

Table 1

Table 1

Table 2 shows the distribution of CYP2D6 genotypes. The most frequent genotypes were *1/*1 (73.7%), *1/*5 (13.9%) and *1/*2 (6.3%). All nine other genotypes showed frequencies below 2.1%, among them the constellation (*5/*5) indicative for the single poor metabolizer (0.4%) found in this study. The distribution of the various genotypes agreed closely with that predicted from the Hardy–Weinberg Law.

Table 2

Table 2

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CYP2C19 genotyping

The distributions of CYP2C19 allele and genotype frequencies are summarized in Tables 3 and 4. Because of failure of PCR analysis in 12 samples, only 227 subjects could be analysed. The wild-type allele *1 had the highest frequency (50.2%), followed by the non-functional alleles *2 (35.5%) and *3 (14.3%). All six possible genotypes were found, three of them specifing extensive metabolizers (74.4%) and poor metabolizers (25.6%), respectively. The most frequent extensive metabolizer genotype was *1/ *2 with 36.5%, followed by *1/ *1 with 26% and *1/ *3 with 11.9%. The poor metabolizer genotypes *2/ *2 and *2/ *3 both had frequencies of 11.5% while *3/ *3 was less frequent with 2.6%.

Table 3

Table 3

Table 4

Table 4

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CYP2E1 genotyping

Because of failure of PCR analysis in two samples, only 237 subjects could be analysed. Only one subject had the rare c2 allele (a heterozygote) giving an overall allele frequency of 0.2%.

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Discussion

Our study is the first to have documented the distribution of CYP2D6, CYP2C19 and CYP2E1 genotypes and alleles in a population of Australian Aborigines. It provides evidence that the genotype distribution and predicted phenotype frequencies for CYP2D6 and CYP2C19 in Aborigines are similar to those for East Asian populations, but different from those for Caucasians.

The frequency of poor metabolizers for CYP2D6 is 5–10% in Caucasians, but only 0.4% in Aborigines. Two factors are responsible for this difference. First, the frequency of the non-functional allele CYP2D6*4 is 19.5% in Caucasians (Griese et al., 1998) in contrast to 1.5% in Aborigines. Second, in Aborigines only three of a possible seven non-functional alleles (*4, *5 and *16) were found. The alleles *5 and *16 are characterized by large deletions of CYP2D6 sequences and their frequencies (approximately 5% for *5 and < 1% for *16) were similar in the Aborigines to data for all populations previously studied (Masimirembwa & Hasler, 1997). This suggests that recombinations in the CYP2D6 gene group resulting in gene deletions occurred before the evolutionary separation of the three largest races approximately 150 000 years ago or that they occur at a constant rate in all populations (Bertilsson, 1995).

The frequencies for most of the CYP2D6 alleles analysed in this study do not differ between Aborigines and Orientals, supporting the hypothesis that Aborigines originated from East Asia. However, the frequency for *10 was only 0.8% for Aborigines which contrasted markedly to the 33–50% reported for East Asian populations (Johansson et al., 1994;Meyer & Zanger, 1997). A founder effect seems to be an unlikely explanation for these findings given that, because of its high frequency, the *10 allele would have been significant in the gene pool of the small groups of migrants who originally colonized northern Australia. A more convincing alternative hypothesis is selection by diet. Since the *10 enzyme has a decreased stability and catalytic activity (Johansson et al., 1994), its ability to detoxify phytoalexins (toxic xenobiotics synthesized by plants) could be reduced. In such case, carriers of *10 would have been at a selective disadvantage in a new environment. However, the low frequency of the *10 allele in Aborigines suggests that if they separated from the Oriental race, it must have been at a very early time.

CYP2D6*17, a further variant with decreased function, is unlikely to be important in this context because of the low frequency of this allele (0.2%) in Aborigines. Since it could not be found in non-African populations studied previously, the most likely explanation for its presence in one Aborigine is admixture with African/American Black people. Allele CYP2D6*2xN, indicative for the ultrarapid metabolizer phentoype was not seen in the Aborigines. This is similar to the situation in most Caucasian and Oriental populations where the frequency is 1–3.5% (Meyer & Zanger, 1997;Griese et al., 1998).

Since we were not in a position to assess CYP2D6 phenotype directly in the Aborigines, we may have overlooked the presence of new mutations that could affect the metabolic capacity of CYP2D6 in this population. Nevertheless, based on genotyping, some conclusions can be drawn. The CYP2D6 data indicate that the metabolism of drugs that are substrates for CYP2D6 should be different in Aborigines to that in other major races for two reasons. By contrast to other populations, the proportion of *1/*1 homozygotes in Aborigines was 73.7%, and many mutations that lead to loss or impairment of function had very low frequencies or were absent. In addition, the shift in the metabolic ratio to higher values that occurs in Orientals (and results in a lower metabolic clearance) is unlikely to be present in the Aborigines, since the frequency of the *10 allele was very low (0.8%).

In contrast to the CYP2D6 data, allele distribution and predicted phenotype frequencies for CYP2C19 were very similar between Aborigine, Oriental (de Morais et al., 1995;Goldstein et al., 1997;Xiao et al., 1997;Watanabe et al., 1998) and Polynesian (Wanwimolruk et al., 1998) populations, but differed considerably from those for Caucasians (Goldstein et al., 1997;Masimirembwa & Hasler, 1997). The frequencies of the nonfunctional CYP2C19*2 (35.5%) and *3 (14.3%) alleles were similar to, or slightly greater than values reported for Orientals (23–39% for *2, and 4–11% for *3) (de Morais et al., 1995;Xiao et al., 1997;Watanabe et al., 1998). In contrast, the frequency of *2 in Caucasians is low (13%) and *3 could not be found (Goldstein et al., 1997). Therefore, the predicted frequency of the poor metabolizer phenotype for 2C19 (Table 4) was much greater in Aborigines (25.2%) than observed for Caucasians (< 5%) (Goldstein et al., 1997) (Masimirembwa & Hasler 1997), while being similar to that in both Orientals (13–23%) (de Morais et al., 1995;Xiao et al., 1997;Watanabe et al., 1998) and Indonesians (15.4%) (Setiabudy et al., 1994).

Only 0.2% of Australian Aborigines were found to have the CYP2E1 c2 allele. This is below the reported allele frequencies for African–Americans (1–2%), Caucasians (2–4%) and Orientals (19–36%) (Carr et al., 1996). The marked difference between the Australian Aborigine and Orientals contrasts to the situation with CYP2D6 and CYP2C19. Genetic drift may provide an explanation for this difference.

An understanding of inter-ethnic differences in genotypes is important for prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics (Linder & Valdes, 1999;Wolf & Smith, 1999). Since the Aborigines were almost exclusively of the extensive metabolizer phenotype for CYP2D6, their response to therapeutic agents that require metabolic activation should be good, and toxicity associated with the poor metabolizer phenotype in other populations should be absent. For CYP2C19, the poor metabolizer phenotype is suggested to have lower clearance for some drugs and this may in turn prolong or increase the drug effect (Caraco et al., 1996;Watanabe et al., 1998). Consequently, poor metabolizers may require lower doses of drugs such as diazepam (Bertilsson et al., 1989). In the case of proguanil, poor metabolizer and extensive metabolizer phenotypes may result in different side-effects or toxicity profiles (Kaneko et al., 1999). Since the Australian Aborigines have a much greater proportion of the poor metabolizer phenotype than Caucasians, their metabolic handling of CYP2C19 drug substrates may be very different. It is interesting to note that a recent study has suggested that the CYP2C19*2 allele results in lower clearance of phenytoin in Japanese epileptic patients (Hashimoto et al., 1996;Watanabe et al., 1998). While CYP2C9 is generally accepted to be the major CYP isoform responsible for the metabolism of this drug (Miners & Birkett, 1998), both CYP2C9 and CYP2C19 have been associated with a reduced Vmax for phenytoin metabolism in Japanese patients (Hashimoto et al., 1996;Watanabe et al., 1998). Since the CYP2C19*2 mutation represented some 36% of slow alleles in the Australian Aborigine, we speculate that the Vmax for hepatic phenytoin 4-hydroxylation may be low in poor metabolizer Aborigines. This, in turn, would be expected to result in a lower dose requirement for phenytoin in this population. However, further work is needed to test this hypothesis.

Associations between the c2 polymorphism in CYP2E1 and carcinogenesis (Kato et al., 1992;Hirvonen et al., 1993;Persson et al., 1993;Uematsu et al., 1994;Hung et al., 1997) and alcoholic liver disease (Maezawa et al., 1994;Tsutsumi et al., 1994a;Pirmohamed et al., 1995) have been studied but remain controversial. Since CYP2E1 mutations were extremely low, any influence of the CYP2E1 gene on diseases such as cancer or alcoholic liver disease, or on hepatotoxicity following the use of halogenated anaesthetics in this population is likely to be minimal.

In conclusion, our data suggest a close genetic relationship between East Asian populations and Aborigines. In this regard, Macknight has suggested migration of the Aborigine to the Kimberley region of Western Australia via the Indonesian archipelago (Macknight, 1976) some 30 000 years ago (Morwood & Hobbs, 1995), although because of difficulties with the accuracy of radiocarbon dating, others suggest that an earlier date of 55–60 000 years ago may be more appropriate (Flannery, 1994). Consistent with this hypothesis is the low prevalence (approximately 1%) of the poor metabolizer trait for CYP2D6 in East Asian populations. One explanation could be that a functional CYP2D6 system is essential to detoxify phytoalexins present in local plants that served as a part of the diet for the Aborigine over many centuries. Diet therefore could be an important environmental factor and a selection force favouring functional CYP2D6 proteins and the extensive metabolizer phenotype. The poor metabolizer phenotype could only survive at a low frequency if, as discussed above, recombinations in the CYP2D6 gene group occurred at a constant rate, providing the non-functional CYP2D6*5 deletion allele, or alternatively if admixture with other populations occurred. Finally, it should be noted that our study population was a relatively homogeneous group, and that further studies of other population groups of Australian Aborigines are needed.

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Acknowledgements

This work was supported by a grant from The Medical Research Fund of Western Australia and the Robert-Bosch Foundation (Stuttgart/Germany). The authors thank the Busselton Population Medical Research Foundation for access to the data from the 1995 Health Survey of the Aboriginal Community that was studied. We are also grateful to all those members of the Community who participated in our study.

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Keywords:

CYP2D6; CYP2C19; CYP2E1; genetic polymorphism; Australian Aborigine

© 2001 Lippincott Williams & Wilkins, Inc.