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%.
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.
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.
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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